Indazole derivatives as inhibitors of sarm1

ABSTRACT

The present disclosure provides compounds of formula (I) and methods useful for inhibiting SARM1 and/or treating and/or preventing axonal degeneration.

BACKGROUND

Axonal degeneration is a hallmark of several neurological disordersincluding peripheral neuropathy, traumatic brain injury, andneurodegenerative diseases (Gerdts et al., SARM1 activation triggersaxon degeneration locally via NAD(+) destruction. Science 348 2016, pp.453-457, hereby incorporated by reference in its entirety).Neurodegenerative diseases and injuries are devastating to both patientsand caregivers. Costs associated with these diseases currently exceedseveral hundred billion dollars annually in the Unites States alone.Since the incidence of many of these diseases and disorders increaseswith age, their incidence is rapidly increasing as demographics change.

SUMMARY

The present disclosure provides technologies useful, among other things,for treating and/or preventing neurodegeneration (e.g., for reducingaxonal degeneration). In some embodiments, provided technologies inhibitSARM1.

In some embodiments, the present disclosure provides certain compoundsand/or compositions that are useful in medicine, and particularly fortreating neurodegeneration (e.g., for reducing axonal degeneration).

In some embodiments, the present disclosure provides compounds having astructure as set forth in Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

-   Ring A, together with the carbon atoms to which it is fused, is a    6-membered aryl ring or a 6-membered heteroaryl ring having 1-2    nitrogen atoms;-   X is selected from C-Rx and N;-   L is an optionally substituted C₁₋₄ aliphatic chain wherein one or    two carbon atoms in the aliphatic chain are optionally replaced by a    group independently selected from —O—, —N(R)—, —S—,    —C(O)—,—C(O)N(R)—, —N(R)C(O)—, —C(O)O—, —OC(O)—, —S(O)₂N(R)—,    —N(R)S(O)₂-, and a bivalent 3- to 5-membered monocyclic, bicyclic,    or bridged bicyclic carbocyclic ring;-   R¹ is an optionally substituted group selected from a 3- to    7-membered saturated or partially unsaturated heterocyclic ring    having 1-3 heteroatoms independently selected from oxygen, nitrogen,    and sulfur and a 5- to 6-membered heteroaryl ring having 1-3    heteroatoms independently selected from oxygen, nitrogen, and    sulfur;-   R² is hydrogen, halogen, N(R′)₂, OR′, or an optionally substituted    group selected from C₁₋₆ aliphatic, a 3- to 7-membered saturated or    partially unsaturated heterocyclic ring having 1-3 heteroatoms    independently selected from oxygen, nitrogen, and sulfur, phenyl, a    5- to 6-membered heteroaryl ring having 1-3 heteroatoms    independently selected from oxygen, nitrogen, and sulfur, a 8- to    10-membered bicyclic saturated, partially unsaturated or aryl    carbocyclic ring, a 8- to 10-membered bicyclic saturated or    partially unsaturated heterocyclic ring having 1-3 heteroatoms    independently selected from oxygen, nitrogen, and sulfur, and a 8-    to 10-membered bicyclic heteroaryl ring having 1-3 heteroatoms    independently selected from oxygen, nitrogen, and sulfur;-   R³ is independently hydrogen or an optionally substituted group    selected from C₁₋₆ aliphatic, a 3-to 7-membered saturated or    partially unsaturated heterocyclic ring having 1-3 heteroatoms    independently selected from oxygen, nitrogen, and sulfur, phenyl,    and a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms    independently selected from oxygen, nitrogen, and sulfur;-   each R^(x) and R^(y) is independently selected from hydrogen,    halogen, cyano, OR″, SR″, N(R″)₂, and optionally substituted C₁₋₄    aliphatic;-   each of R, R′, and R″ is independently hydrogen or an optionally    substituted group selected from C₁₋₆ aliphatic, a 3- to 7-membered    saturated or partially unsaturated heterocyclic ring having 1-3    heteroatoms independently selected from oxygen, nitrogen, and    sulfur, phenyl, and a 5- to 6-membered heteroaryl ring having 1-3    heteroatoms independently selected from oxygen, nitrogen, and    sulfur; or:    -   R and R², together with the intervening atom(s) to which they        are attached, form an optionally substituted 3- to 7-membered        monocyclic heterocyclic ring having 0-2 additional heteroatoms        independently selected from oxygen, nitrogen, and sulfur; or    -   two R′ groups, together with the nitrogen atom to which they are        attached, form an optionally substituted 3- to 7-membered        monocyclic heterocyclic ring having 0-2 additional heteroatoms        independently selected from oxygen, nitrogen, and sulfur; or    -   two R″ groups, together with the nitrogen atom to which they are        attached, form an optionally substituted 3- to 7-membered        monocyclic heterocyclic ring having 0-2 additional heteroatoms        independently selected from oxygen, nitrogen, and sulfur; and-   n is 0, 1, or 2.

In some embodiments, provided compounds have structures of Formulae I-a,I-a-i, I-a-ii, I-a-iii, I-a-iv, I-a-v, I-a-vi, I-a-vii, I-a-viii,I-a-ix, I-a-x, I-a-xi, I-a-xii, I-a-xiii, I-a-xiv, I-a-xv, I-b, I-b-i,I-b-ii, I-b-iii, I-b-iv, I-b-v, I-b-vi, I-b-vii, I-b-viii, I-b-ix,I-b-x, I-b-xi, I-b-xii, I-b-xiii, I-b-xiv, I-b-xv, I-c, I-c-i, I-c-ii,I-c-iii, I-c-iv, I-c-v, I-c-vi, I-c-vii, I-c-viii, I-c-ix, I-c-x,I-c-xi, I-c-xii, I-c-xiii, I-c-xiv, I-c-xv, I-d, I-d-i, I-d-ii, I-d-iii,I-d-iv, I-d-v, I-d-vi, I-d-vii, I-d-viii, I-d-ix, I-d-x, I-d-xi,I-d-xii, I-d-xiii, I-d-xiv, I-d-xv, I-e, I-e-i, I-e-ii, I-e-iii, I-e-iv,I-e-v, I-e-vi, I-e-vii, I-e-viii, I-e-ix, I-e-x, I-e-xi, I-e-xii,I-e-xiii, I-e-xiv, I-e-xv, I-f, I-f-i, I-f-ii, I-f-iii, I-f iv, I-f-v,I-f-vi, I-f-vii, I-f-viii, I-f-ix, I-f-x, I-f-xz, I-f-xii, I-f-xiii,I-f-xiv, I-f-xv, I-g, I-g-i, I-g-ii, I-g-iii, I-g-iv, I-g-v, I-g-vi,I-g-vii, I-g-viii, I-g-ix, I-g-x, I-g-xi, I-g-xii, I-g-xiii, I-g-xiv,and I-g-xv, as set forth below.

In some embodiments, provided compounds have the structure of FormulaII:

or a pharmaceutically acceptable salt thereof, wherein:

-   R¹ is a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms    independently selected from oxygen, nitrogen, and sulfur, wherein    the 5- to 6-membered heteroaryl ring is optionally substituted with    fluorine or methyl;-   R² is a 5- to 6-membered heteroaryl ring having 1 heteroatom    selected from nitrogen and sulfur, or phenyl, wherein the 5- to    6-membered heteroaryl ring or phenyl is optionally substituted with    1-2 groups selected from fluorine and chlorine;-   R⁴ is hydrogen or methyl;-   Q is N or CH;-   X, Y and Z are independently CR⁵ or a nitrogen atom, provided that    no more than two X, Y and Z are nitrogen atoms; and-   R⁵ is hydrogen or methyl.

In a further embodiment, the compound is selected from:

or a pharmaceutically acceptable salt thereof.

In some embodiments, one or more compounds of Formula I/II is providedand/or utilized in a solid form (e.g., a crystal form or an amorphousform).

In some embodiments, the present disclosure provides compositions thatcomprise and/or deliver a compound of Formula I/II (e.g., in a form asdescribed herein), a prodrug or active metabolite thereof.

In some embodiments, the present disclosure provides compositions thatcomprise and/or deliver a compound of Formula I/II. In some embodiments,such compositions are pharmaceutical compositions that include at leastone pharmaceutically acceptable carrier, diluent or excipient.

In some embodiments, provided SARM1 inhibitors reduce or inhibit bindingof NAD+ by SARM1. In some embodiments, provided SARM1 inhibitors bind toSARM1 within a pocket comprising one or more catalytic residues (e.g., acatalytic cleft of SARM1).

In some embodiments, provided compounds and/or compositions inhibitactivity of SARM1. Alternatively, or additionally, in some embodiments,provided compounds alleviate one or more attributes ofneurodegeneration. In some embodiments, the present disclosure providesmethods of treating a neurodegenerative disease or disorder associatedwith axonal degeneration.

In some embodiments, one or more compounds and/or compositions asdescribed herein are useful, for example, in the practice of medicine.In some embodiments, one or more compounds and/or compositions asdescribed herein are useful, for example, to treat, prevent, orameliorate axonal degeneration (e.g., one or more features orcharacteristics thereof). In some embodiments, one or more compoundsand/or compositions as described herein are useful, for example, toinhibit axonal degeneration, including axonal degeneration that resultsfrom reduction or depletion of NAD+. In some embodiments, one or morecompounds and/or compositions as described herein are useful, forexample, to prevent the axon distal to an axonal injury fromdegenerating.

In some embodiments, one or more compounds and/or compositions asdescribed herein are useful, for example, to treat one or moreneurodegenerative diseases, disorders or conditions selected from thegroup consisting of neuropathies and axonopathies. In some embodiments,one or more compounds and/or compositions as described herein areuseful, for example, to treat a neuropathy or axonopathy associated withaxonal degeneration. In some embodiments, a neuropathy associated withaxonal degeneration is a hereditary or congenital neuropathy oraxonopathy. In some embodiments, a neuropathy associated with axonaldegeneration results from a de novo or somatic mutation. In someembodiments, a neuropathy associated with axonal degeneration isselected from a list contained herein. In some embodiments, a neuropathyor axonopathy is associated with axonal degeneration, including, but notlimited to, Parkinson’s disease, Parkinsonian syndromes or Parkinson’splus syndromes such as, for example, Multiple System Atrophy (MSA),Progressive Supranuclear Palsy (PSP), and corticobasal degeneration,Alzheimer’s disease, Herpes infection, diabetes, amyotrophic lateralsclerosis (ALS), a demyelinating disease such as, for example, multiplesclerosis, ischemia or stroke, chemical injury, thermal injury, andAIDS.

In some embodiments, subjects to which a compound or composition asdescribed herein is administered may be or comprise subjects sufferingfrom or susceptible to a neurodegenerative disease, disorder orcondition. In some embodiments, a neurodegenerative disease, disorder orcondition may be or comprise a traumatic neuronal injury. In someembodiments, a traumatic neuronal injury is blunt force trauma, aclosed-head injury, an open head injury, exposure to a concussive and/orexplosive force, a penetrating injury in or to the brain cavity orinnervated region of the body. In some embodiments, a traumatic neuronalinjury is a force which causes axons to deform, stretch, crush or sheer.

In some embodiments, provided methods comprise administering a compounddescribed herein to a patient in need thereof. In some such embodiments,the patient is at risk of developing a condition characterized by axonaldegeneration. In some embodiments, the patient has a conditioncharacterized by axonal degeneration. In some embodiments, the patienthas been diagnosed with a condition characterized by axonaldegeneration.

In some embodiments, provided methods comprise administering acomposition as described herein to a patient population in need thereof.In some embodiments, the population is drawn from individuals who engagein activities where the potential for traumatic neuronal injury is high.In some embodiments, the population is drawn from athletes who engage incontact sports or other high-risk activities

In some embodiments, the patient is at risk of developing aneurodegenerative disorder. In some embodiments the patient is elderly.In some embodiments, the patient is known to have a genetic risk factorfor neurodegeneration.

In certain embodiments, the present disclosure provides compounds thatare useful, for example, as analytical tools, as probes in biologicalassays, or as therapeutic agents in accordance with the presentdisclosure. Compounds provided by this disclosure are also useful forthe study of SARM1 function in biological and pathological phenomena andthe comparative evaluation of new SARM1 activity inhibitors in vitro orin vivo.

In some embodiments, one or more compounds and/or compositions asdescribed herein are useful, for example, as a method for inhibiting thedegradation of neurons derived from a subject. In some embodiments, oneor more compounds and/or compositions as described herein are useful forinhibiting the degeneration of a neuron, or a portion thereof, culturedin vitro. In some embodiments, one or more compounds and/or compositionsas described herein are useful as stabilizing agents to promote in vitroneuronal survival.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 illustrates the structure of the SARM1 protein.

DEFINITIONS

Aliphatic: The term “aliphatic” refers to a straight-chain (i.e.,unbranched) or branched, substituted or unsubstituted hydrocarbon chainthat is completely saturated or that contains one or more units ofunsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon thatis completely saturated or that contains one or more units ofunsaturation, but which is not aromatic (also referred to herein as“carbocycle” or “cycloaliphatic”) Unless otherwise specified, aliphaticgroups contain 1-6 aliphatic carbon atoms. In some embodiments,aliphatic groups contain 1-5 aliphatic carbon atoms. In otherembodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. Instill other embodiments, aliphatic groups contain 1-3 aliphatic carbonatoms, and in yet other embodiments, aliphatic groups contain 1-2aliphatic carbon atoms. In some embodiments, “cycloaliphatic” (or“carbocycle”) refers to a monocyclic C₃-C₈ hydrocarbon or a bicyclicC₇-C₁₀ hydrocarbon that is completely saturated or that contains one ormore units of unsaturation, but which is not aromatic. Suitablealiphatic groups include, but are not limited to, linear or branched,substituted or unsubstituted alkyl, alkenyl, alkynyl, alkylene,alkenylene, alkynylene groups and hybrids thereof.

Alkyl: The term “alkyl”, used alone or as part of a larger moiety,refers to a saturated, optionally substituted straight or branched chainor cyclic hydrocarbon group having 1-12, 1-10, 1-8, 1-6, 1-4, 1-3, or1-2 carbon atoms. The term “cycloalkyl” refers to an optionallysubstituted saturated ring system of about 3 to about 10 ring carbonatoms. Exemplary monocyclic cycloalkyl rings include cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

Alkylene: The term “alkylene” refers to a bivalent alkyl group. In someembodiments, “alkylene” is a bivalent straight or branched alkyl group.In some embodiments, an “alkylene chain” is a polymethylene group, i.e.,—(CH₂)_(n)—, wherein n is a positive integer, e.g., from 1 to 6, from 1to 4, from 1 to 3, from 1 to 2, or from 2 to 3. An optionallysubstituted alkylene chain is a polymethylene group in which one or moremethylene hydrogen atoms is optionally replaced with a substituent.Suitable substituents include those described below for a substitutedaliphatic group and also include those described in the specificationherein. It will be appreciated that two substituents of the alkylenegroup may be taken together to form a ring system. In certainembodiments, two substituents can be taken together to form a 3- to7-membered ring. The substituents can be on the same or different atoms.

Alkenyl: The term “alkenyl”, used alone or as part of a larger moiety,refers to an optionally substituted straight or branched chain or cyclichydrocarbon group having at least one double bond and having 2-12, 2-10,2-8, 2-6, 2-4, or 2-3 carbon atoms. The term “cycloalkenyl” refers to anoptionally substituted non-aromatic monocyclic or multicyclic ringsystem containing at least one carbon-carbon double bond and havingabout 3 to about 10 carbon atoms. Exemplary monocyclic cycloalkenylrings include cyclopentyl, cyclohexenyl, and cycloheptenyl.

Alkynyl: The term “alkynyl”, used alone or as part of a larger moiety,refers to an optionally substituted straight or branched chainhydrocarbon group having at least one triple bond and having 2-12, 2-10,2-8, 2-6, 2-4, or 2-3 carbon atoms.

Aryl: The term “aryl” refers to monocyclic and bicyclic ring systemshaving a total of five to fourteen ring members, wherein at least onering in the system is aromatic and wherein each ring in the systemcontains three to seven ring members. The term “aryl” may be usedinterchangeably with the term “aryl ring”. In certain embodiments of thepresent invention, “aryl” refers to an aromatic ring system whichincludes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl andthe like, which may bear one or more substituents. Also included withinthe scope of the term “aryl”, as it is used herein, is a group in whichan aromatic ring is fused to one or more non-aromatic carbocyclic orheterocyclic rings, such as indanyl, phthalimidyl, naphthimidyl,phenanthridinyl, tetrahydronaphthyl, imidazolidinyl, imidazolidin-2-one,and the like.

Binding: It will be understood that the term “binding”, as used herein,typically refers to a non-covalent association between or among two ormore entities. “Direct” binding involves physical contact betweenentities or moieties; indirect binding involves physical interaction byway of physical contact with one or more intermediate entities. Bindingbetween two or more entities can typically be assessed in any of avariety of contexts - including where interacting entities or moietiesare studied in isolation or in the context of more complex systems(e.g., while covalently or otherwise associated with a carrier entityand/or in a biological system or cell).

Biological Sample: As used herein, the term “biological sample”typically refers to a sample obtained or derived from a biologicalsource (e.g., a tissue or organism or cell culture) of interest, asdescribed herein. In some embodiments, a source of interest comprises anorganism, such as an animal or human. In some embodiments, a biologicalsample is or comprises biological tissue or fluid. In some embodiments,a biological sample may be or comprise bone marrow; blood; blood cells;ascites; tissue or fine needle biopsy samples; cell-containing bodyfluids; free floating nucleic acids; sputum; saliva; urine;cerebrospinal fluid, peritoneal fluid; pleural fluid; feces; lymph;gynecological fluids; skin swabs; vaginal swabs; oral swabs; nasalswabs; washings or lavages such as a ductal lavages or broncheoalveolarlavages; aspirates; scrapings; bone marrow specimens; tissue biopsyspecimens; surgical specimens; feces, other body fluids, secretions,and/or excretions; and/or cells therefrom, etc. In some embodiments, abiological sample is or comprises cells obtained from an individual. Insome embodiments, obtained cells are or include cells from an individualfrom whom the sample is obtained. In some embodiments, a sample is a“primary sample” obtained directly from a source of interest by anyappropriate means. For example, in some embodiments, a primarybiological sample is obtained by methods selected from the groupconsisting of biopsy (e.g., fine needle aspiration or tissue biopsy),surgery, collection of body fluid (e.g., blood, lymph, feces etc.), etc.In some embodiments, as will be clear from context, the term “sample”refers to a preparation that is obtained by processing (e.g., byremoving one or more components of and/or by adding one or more agentsto) a primary sample. For example, filtering using a semi-permeablemembrane. Such a “processed sample” may comprise, for example, nucleicacids or proteins extracted from a sample or obtained by subjecting aprimary sample to techniques such as amplification or reversetranscription of mRNA, isolation and/or purification of certaincomponents, etc.

Biomarker: The term “biomarker” is used herein to refer to a to anentity, event, or characteristic whose presence, level, degree, type,and/or form, correlates with a particular biological event or state ofinterest, so that it is considered to be a “marker” of that event orstate. To give but a few examples, in some embodiments, a biomarker maybe or comprise a marker for a particular disease state, or forlikelihood that a particular disease, disorder or condition may develop,occur, or reoccur. In some embodiments, a biomarker may be or comprise amarker for a particular disease or therapeutic outcome, or likelihoodthereof. Thus, in some embodiments, a biomarker is predictive, in someembodiments, a biomarker is prognostic, in some embodiments, a biomarkeris diagnostic, of the relevant biological event or state of interest. Abiomarker may be or comprise an entity of any chemical class, and may beor comprise a combination of entities. For example, in some embodiments,a biomarker may be or comprise a nucleic acid, a polypeptide, a lipid, acarbohydrate, a small molecule, an inorganic agent (e.g., a metal orion), or a combination thereof. In some embodiments, a biomarker is acell surface marker. In some embodiments, a biomarker is intracellular.In some embodiments, a biomarker is detected outside of cells (e.g., issecreted or is otherwise generated or present outside of cells, e.g., ina body fluid such as blood, urine, tears, saliva, cerebrospinal fluid,etc. In some embodiments, a biomarker may be or comprise a genetic orepigenetic signature. In some embodiments, a biomarker may be orcomprise a gene expression signature.

In some embodiments, a biomarker may be or comprise a marker forneurodegeneration, or for likelihood that a neurodegenerative disease,disorder or condition may develop, occur, or reoccur. In someembodiments, a biomarker may be or comprise a marker ofneurodegeneration a therapeutic outcome, or likelihood thereof. Thus, insome embodiments, a biomarker is predictive, in some embodiments, abiomarker is prognostic, in some embodiments, a biomarker is diagnostic,of a neurodegenerative disease, disorder or condition. In someembodiments changes in biomarker levels can be detected via cerebralspinal fluid (CSF), plasma and/or serum.

In some embodiments, neurodegeneration may be assessed, for example, bydetecting an increase and/or decrease in the concentration ofneurofilament protein light (NF-L) and/or neurofilament protein heavy(NF—H) (or its phosphorylated form (pNF—H)) contained in the cerebralspinal fluid of a subject. In some embodiments, the incidence and/orprogression of neurodegeneration can be assessed via positron emissiontomography (PET) with a synaptic vesicle glycoprotein 2a (SV2A) ligand.In some embodiments, a detectable change in constitutive NAD and/orcADPR levels in neurons can be used to assess neurodegeneration.

In some embodiments, a detectable change in one or moreneurodegeneration associated proteins in a subject, relative to ahealthy reference population can be used as a biomarker ofneurodegeneration. Such proteins include, but are not limited to,albumin, amyloid-β (Aβ)38, Aβ40, Aβ42, glial fibrillary acid protein(GFAP), heart-type fatty acid binding protein (hFABP), monocytechemoattractin protein (MCP)-1, neurogranin, neuron specific enolayse(NSE), soluble amyloid precursor protein (sAPP)α, sAPPβ, solubletriggering receptor expressed on myeloid cells (sTREM) 2, phospho-tau,and/or total-tau. In some embodiments, an increase in cytokines and/orchemokines, including, but not limited to, Ccl2, Ccl7, Ccl12, Csf1,and/or Il6, can be used as a biomarker of neurodegeneration.

Carrier: As used herein, the term “carrier” refers to a diluent,adjuvant, excipient, or vehicle with which a composition isadministered. In some exemplary embodiments, carriers can includesterile liquids, such as, for example, water and oils, including oils ofpetroleum, animal, vegetable or synthetic origin, such as, for example,peanut oil, soybean oil, mineral oil, sesame oil and the like. In someembodiments, carriers are or include one or more solid components.

Combination therapy: As used herein, the term “combination therapy”refers to those situations in which a subject is simultaneously exposedto two or more therapeutic regimens (e.g., two or more therapeuticagents). In some embodiments, the two or more regimens may beadministered simultaneously; in some embodiments, such regimens may beadministered sequentially (e.g., all “doses” of a first regimen areadministered prior to administration of any doses of a second regimen);in some embodiments, such agents are administered in overlapping dosingregimens. In some embodiments, “administration” of combination therapymay involve administration of one or more agent(s) or modality(ies) to asubject receiving the other agent(s) or modality(ies) in thecombination. For clarity, combination therapy does not require thatindividual agents be administered together in a single composition (oreven necessarily at the same time), although in some embodiments, two ormore agents, or active moieties thereof, may be administered together ina combination composition, or even in a combination compound (e.g., aspart of a single chemical complex or covalent entity).

Composition: Those skilled in the art will appreciate that the term“composition” may be used to refer to a discrete physical entity thatcomprises one or more specified components. In general, unless otherwisespecified, a composition may be of any form - e.g., gas, gel, liquid,solid, etc.

Domain: The term “domain” as used herein refers to a section or portionof an entity. In some embodiments, a “domain” is associated with aparticular structural and/or functional feature of the entity so that,when the domain is physically separated from the rest of its parententity, it substantially or entirely retains the particular structuraland/or functional feature. Alternatively or additionally, a domain maybe or include a portion of an entity that, when separated from that(parent) entity and linked with a different (recipient) entity,substantially retains and/or imparts on the recipient entity one or morestructural and/or functional features that characterized it in theparent entity. In some embodiments, a domain is a section or portion ofa molecule (e.g., a small molecule, carbohydrate, lipid, nucleic acid,or polypeptide). In some embodiments, a domain is a section of apolypeptide; in some such embodiments, a domain is characterized by aparticular structural element (e.g., a particular amino acid sequence orsequence motif, α-helix character, β-sheet character, coiled-coilcharacter, random coil character, etc.), and/or by a particularfunctional feature (e.g., binding activity, enzymatic activity, foldingactivity, signaling activity, etc.).

Dosage form or unit dosage form: Those skilled in the art willappreciate that the term “dosage form” may be used to refer to aphysically discrete unit of an active agent (e.g., a therapeutic ordiagnostic agent) for administration to a subject. Typically, each suchunit contains a predetermined quantity of active agent. In someembodiments, such quantity is a unit dosage amount (or a whole fractionthereof) appropriate for administration in accordance with a dosingregimen that has been determined to correlate with a desired orbeneficial outcome when administered to a relevant population (i.e.,with a therapeutic dosing regimen). Those of ordinary skill in the artappreciate that the total amount of a therapeutic composition or agentadministered to a particular subject is determined by one or moreattending physicians and may involve administration of multiple dosageforms.

Dosing regimen or therapeutic regimen: Those skilled in the art willappreciate that the terms “dosing regimen” and “therapeutic regimen” maybe used to refer to a set of unit doses (typically more than one) thatare administered individually to a subject, typically separated byperiods of time. In some embodiments, a given therapeutic agent has arecommended dosing regimen, which may involve one or more doses. In someembodiments, a dosing regimen comprises a plurality of doses each ofwhich is separated in time from other doses. In some embodiments,individual doses are separated from one another by a time period of thesame length; in some embodiments, a dosing regimen comprises a pluralityof doses and at least two different time periods separating individualdoses. In some embodiments, all doses within a dosing regimen are of thesame unit dose amount. In some embodiments, different doses within adosing regimen are of different amounts. In some embodiments, a dosingregimen comprises a first dose in a first dose amount, followed by oneor more additional doses in a second dose amount different from thefirst dose amount. In some embodiments, a dosing regimen comprises afirst dose in a first dose amount, followed by one or more additionaldoses in a second dose amount same as the first dose amount. In someembodiments, a dosing regimen is correlated with a desired or beneficialoutcome when administered across a relevant population (i.e., is atherapeutic dosing regimen).

Excipient: as used herein, refers to a non-therapeutic agent that may beincluded in a pharmaceutical composition, for example, to provide orcontribute to a desired consistency or stabilizing effect. Suitablepharmaceutical excipients include, for example, starch, glucose,lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodiumstearate, glycerol monostearate, talc, sodium chloride, dried skim milk,glycerol, propylene, glycol, water, ethanol and the like.

Heteroaryl: The terms “heteroaryl” and “heteroar-”, used alone or aspart of a larger moiety, e.g., “heteroaralkyl”, or “heteroaralkoxy”,refer to groups having 5 to 10 ring atoms, preferably 5, 6, 9, or 10ring atoms; having 6, 10, or 14 π-electrons shared in a cyclic array;and having, in addition to carbon atoms, from one to five heteroatoms.The term “heteroatom” refers to nitrogen, oxygen, or sulfur, andincludes any oxidized form of nitrogen or sulfur, and any quaternizedform of a basic nitrogen. Heteroaryl groups include, without limitation,thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl,tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl,thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl,purinyl, naphthyridinyl, and pteridinyl. The terms “heteroaryl” and“heteroar-”, as used herein, also include groups in which aheteroaromatic ring is fused to one or more aryl, cycloaliphatic, orheterocyclyl rings. Nonlimiting examples include indolyl, isoindolyl,benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl,benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl,quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl,phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. Aheteroaryl group may be mono- or bicyclic. The term “heteroaryl” may beused interchangeably with the terms “heteroaryl ring”, “heteroarylgroup”, or “heteroaromatic”, any of which terms include rings that areoptionally substituted. The term “heteroaralkyl” refers to an alkylgroup substituted by a heteroaryl, wherein the alkyl and heteroarylportions independently are optionally substituted.

Heterocycle: As used herein, the terms “heterocycle”, “heterocyclyl”,“heterocyclic radical”, and “heterocyclic ring” are used interchangeablyand refer to a stable 3- to 8-membered monocyclic or 7-10-memberedbicyclic heterocyclic moiety that is either saturated or partiallyunsaturated, and having, in addition to carbon atoms, one or more, suchas one to four, heteroatoms, as defined above. When used in reference toa ring atom of a heterocycle, the term “nitrogen” includes a substitutednitrogen. As an example, in a saturated or partially unsaturated ringhaving 0-3 heteroatoms selected from oxygen, sulfur and nitrogen, thenitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as inpyrrolidinyl), or NR⁺ (as in N-substituted pyrrolidinyl). A heterocyclicring can be attached to its pendant group at any heteroatom or carbonatom that results in a stable structure and any of the ring atoms can beoptionally substituted. Examples of such saturated or partiallyunsaturated heterocyclic radicals include, without limitation,tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, decahydroquinolinyl,oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl,thiazepinyl, morpholinyl, and thiamorpholinyl. A heterocyclyl group maybe mono-, bi-, tri-, or polycyclic, preferably mono-, bi-, or tricyclic,more preferably mono- or bicyclic. The term “heterocyclylalkyl” refersto an alkyl group substituted by a heterocyclyl, wherein the alkyl andheterocyclyl portions independently are optionally substituted.Additionally, a heterocyclic ring also includes groups in which theheterocyclic ring is fused to one or more aryl rings (e.g.,2,3-dihydrobenzofuran, 2,3-dihydrobenzo[b][1,4]dioxine, etc.).

Inhibitory agent: As used herein, the term “inhibitory agent” refers toan entity, condition, or event whose presence, level, or degreecorrelates with decreased level or activity of a target. In someembodiments, an inhibitory agent may act directly (in which case itexerts its influence directly upon its target, for example, by bindingto the target); in some embodiments, an inhibitory agent may actindirectly (in which case it exerts its influence by interacting withand/or otherwise altering a regulator of the target, so that leveland/or activity of the target is reduced). In some embodiments, aninhibitory agent is one whose presence or level correlates with a targetlevel or activity that is reduced relative to a particular referencelevel or activity (e.g., that observed under appropriate referenceconditions, such as presence of a known inhibitory agent, or absence ofthe inhibitory agent in question, etc.).

Neurodegeneration: As used herein, the term “neurodegeneration” refersto a reduction in one or more features, structures, function, orcharacteristics of a neuron or neuronal tissue. In some embodiments,neurodegeneration is observed as a pathological reduction in anorganism. Those skilled in the art will appreciate thatneurodegeneration is associated with certain diseases, disorders andconditions, including those that affect humans. In some embodiments,neurodegeneration may be transient (e.g., as sometimes occurs inassociation with certain infections and/or chemical or mechanicaldisruptions); in some embodiments, neurodegeneration may be chronicand/or progressive (e.g., as is often associated with certain diseases,disorders or conditions such as, but not limited to, Parkinson’sdisease, amyotrophic lateral sclerosis, multiple sclerosis, Huntingtondisease, or Alzheimer’s disease). In some embodiments, neurodegenerationmay be assessed, for example, by detecting in a subject an increase in abiomarker associated with neurodegeneration. In some embodiments,neurodegeneration may be assessed, for example, by detecting in asubject a decrease in a biomarker associated with neurodegeneration.Alternatively or additionally, in some embodiments, neurodegenerationmay be assessed by magnetic resonance imaging (MRI), biomarkerscontained in cerebral spinal fluid, or other biomarkers observed inpatients. In some embodiments, neurodegeneration is defined as a scoreof below 24 on the mini-mental state examination. In some embodiments,neurodegeneration refers to loss of synapses. In some embodiments,neurodegeneration refers to a reduction in neural tissue relating to atraumatic injury (e.g. exposure to an external force which disrupts theintegrity of the neural tissue). In some embodiments, neurodegenerationrefers to a reduction in peripheral neural tissue. In some embodiments,neurodegeneration refers to a reduction in central nervous tissue.

Oral: The phrases “oral administration” and “administered orally” asused herein have their art-understood meaning referring toadministration by mouth of a compound or composition.

Parenteral: The phrases “parenteral administration” and “administeredparenterally” as used herein have their art-understood meaning referringto modes of administration other than enteral and topicaladministration, usually by injection, and include, without limitation,intravenous, intramuscular, intra-arterial, intrathecal, intracapsular,intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal,subcutaneous, subcuticular, intraarticulare, subcapsular, subarachnoid,intraspinal, and intrasternal injection and infusion.

Partially Unsaturated: As used herein, the term “partially unsaturated”refers to a ring moiety that includes at least one double or triple bondbetween ring atoms. The term “partially unsaturated” is intended toencompass rings having multiple sites of unsaturation, but is notintended to include aromatic (e.g., aryl or heteroaryl) moieties, asherein defined.

Patient: As used herein, the term “patient” refers to any organism towhich a provided composition is or may be administered, e.g., forexperimental, diagnostic, prophylactic, cosmetic, and/or therapeuticpurposes. Typical patients include animals (e.g., mammals such as mice,rats, rabbits, non-human primates, and/or humans). In some embodiments,a patient is a human. In some embodiments, a patient is suffering fromor susceptible to one or more disorders or conditions. In someembodiments, a patient displays one or more symptoms of a disorder orcondition. In some embodiments, a patient has been diagnosed with one ormore disorders or conditions. In some embodiments, the patient isreceiving or has received certain therapy to diagnose and/or to treat adisease, disorder, or condition.

Pharmaceutical composition: As used herein, the term “pharmaceuticalcomposition” refers to an active agent, formulated together with one ormore pharmaceutically acceptable carriers. In some embodiments, theactive agent is present in unit dose amount appropriate foradministration in a therapeutic or dosing regimen that shows astatistically significant probability of achieving a predeterminedtherapeutic effect when administered to a relevant population. In someembodiments, pharmaceutical compositions may be specially formulated foradministration in solid or liquid form, including those adapted for thefollowing: oral administration, for example, drenches (aqueous ornon-aqueous solutions or suspensions), tablets, e.g., those targeted forbuccal, sublingual, and systemic absorption, boluses, powders, granules,pastes for application to the tongue; parenteral administration, forexample, by subcutaneous, intramuscular, intravenous or epiduralinjection as, for example, a sterile solution or suspension, orsustained-release formulation; topical application, for example, as acream, ointment, or a controlled-release patch or spray applied to theskin, lungs, or oral cavity; intravaginally or intrarectally, forexample, as a pessary, cream, or foam; sublingually; ocularly;transdermally; or nasally, pulmonary, and to other mucosal surfaces.

Pharmaceutically acceptable: As used herein, the phrase“pharmaceutically acceptable” refers to those compounds, materials,compositions, and/or dosage forms which are, within the scope of soundmedical judgment, suitable for use in contact with the tissues of humanbeings and animals without excessive toxicity, irritation, allergicresponse, or other problem or complication, commensurate with areasonable benefit/risk ratio.

Pharmaceutically acceptable carrier: As used herein, the term“pharmaceutically acceptable carrier” means apharmaceutically-acceptable material, composition or vehicle, such as aliquid or solid filler, diluent, excipient, or solvent encapsulatingmaterial, involved in carrying or transporting the subject compound fromone organ, or portion of the body, to another organ, or portion of thebody. Each carrier must be “acceptable” in the sense of being compatiblewith the other ingredients of the formulation and not injurious to thepatient. Some examples of materials which can serve aspharmaceutically-acceptable carriers include: sugars, such as lactose,glucose and sucrose; starches, such as corn starch and potato starch;cellulose, and its derivatives, such as sodium carboxymethyl cellulose,ethyl cellulose and cellulose acetate; powdered tragacanth; malt;gelatin; talc; excipients, such as cocoa butter and suppository waxes;oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil,olive oil, corn oil and soybean oil; glycols, such as propylene glycol;polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol;esters, such as ethyl oleate and ethyl laurate; agar; buffering agents,such as magnesium hydroxide and aluminum hydroxide; alginic acid;pyrogen-free water; isotonic saline; Ringer’s solution; ethyl alcohol;pH buffered solutions; polyesters, polycarbonates and/or polyanhydrides;and other nontoxic compatible substances employed in pharmaceuticalformulations.

Pharmaceutically acceptable salt: The term “pharmaceutically acceptablesalt”, as used herein, refers to salts of such compounds that areappropriate for use in pharmaceutical contexts, i.e., salts which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of humans and lower animals without undue toxicity,irritation, allergic response and the like, and are commensurate with areasonable benefit/risk ratio. Pharmaceutically acceptable salts arewell known in the art. For example, S. M. Berge, et al. describespharmaceutically acceptable salts in detail in J. PharmaceuticalSciences, 66: 1-19 (1977). In some embodiments, pharmaceuticallyacceptable salts include, but are not limited to, nontoxic acid additionsalts, which are salts of an amino group formed with inorganic acidssuch as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuricacid and perchloric acid or with organic acids such as acetic acid,maleic acid, tartaric acid, citric acid, succinic acid or malonic acidor by using other methods used in the art such as ion exchange. In someembodiments, pharmaceutically acceptable salts include, but are notlimited to, adipate, alginate, ascorbate, aspartate, benzenesulfonate,benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate,citrate, cyclopentanepropionate, digluconate, dodecylsulfate,ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate,gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, stearate, succinate, sulfate, tartrate,thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and thelike. Representative alkali or alkaline earth metal salts includesodium, lithium, potassium, calcium, magnesium, and the like. In someembodiments, pharmaceutically acceptable salts include, whenappropriate, nontoxic ammonium, quaternary ammonium, and amine cationsformed using counterions such as halide, hydroxide, carboxylate,sulfate, phosphate, nitrate, alkyl having from 1 to 6 carbon atoms,sulfonate and aryl sulfonate.

Prevent or prevention: As used herein, the terms “prevent” or“prevention”, when used in connection with the occurrence of a disease,disorder, and/or condition, refer to reducing the risk of developing thedisease, disorder and/or condition and/or to delaying onset of one ormore characteristics or symptoms of the disease, disorder or condition.Prevention may be considered complete when onset of a disease, disorderor condition has been delayed for a predefined period of time.

Specific: The term “specific”, when used herein with reference to anagent having an activity, is understood by those skilled in the art tomean that the agent discriminates between potential target entities orstates. For example, in some embodiments, an agent is said to bind“specifically” to its target if it binds preferentially with that targetin the presence of one or more competing alternative targets. In manyembodiments, specific interaction is dependent upon the presence of aparticular structural feature of the target entity (e.g., an epitope, acleft, a binding site). It is to be understood that specificity need notbe absolute. In some embodiments, specificity may be evaluated relativeto that of the binding agent for one or more other potential targetentities (e.g., competitors). In some embodiments, specificity isevaluated relative to that of a reference specific binding agent. Insome embodiments, specificity is evaluated relative to that of areference non-specific binding agent. In some embodiments, the agent orentity does not detectably bind to the competing alternative targetunder conditions of binding to its target entity. In some embodiments, abinding agent binds with higher on-rate, lower off-rate, increasedaffinity, decreased dissociation, and/or increased stability to itstarget entity as compared with the competing alternative target(s).

Subject: As used herein, the term “subject” refers to an organism,typically a mammal (e.g., a human, in some embodiments includingprenatal human forms). In some embodiments, a subject is suffering froma relevant disease, disorder or condition. In some embodiments, asubject is susceptible to a disease, disorder, or condition. In someembodiments, a subject displays one or more symptoms or characteristicsof a disease, disorder or condition. In some embodiments, a subject doesnot display any symptom or characteristic of a disease, disorder, orcondition. In some embodiments, a subject is someone with one or morefeatures characteristic of susceptibility to or risk of a disease,disorder, or condition. In some embodiments, a subject is a patient. Insome embodiments, a subject is an individual to whom diagnosis and/ortherapy is and/or has been administered.

Substituted or optionally substituted: As described herein, compounds ofthe invention may contain “optionally substituted” moieties. In general,the term “substituted,” whether preceded by the term “optionally” ornot, means that one or more hydrogens of the designated moiety arereplaced with a suitable substituent. “Substituted” applies to one ormore hydrogens that are either explicit or implicit from the structure(e.g.,

refers to at least

refers to at least

Unless otherwise indicated, an “optionally substituted” group may have asuitable substituent at each substitutable position of the group, andwhen more than one position in any given structure may be substitutedwith more than one substituent selected from a specified group, thesubstituent may be either the same or different at every position.Combinations of substituents envisioned by this invention are preferablythose that result in the formation of stable or chemically feasiblecompounds. The term “stable,” as used herein, refers to compounds thatare not substantially altered when subjected to conditions to allow fortheir production, detection, and, in certain embodiments, theirrecovery, purification, and use for one or more of the purposesdisclosed herein.

Suitable monovalent substituents on a substitutable carbon atom of an“optionally substituted” group are independently halogen; —(CH₂)₀₋₄R°;—(CH₂)₀₋₄OR°; —O(CH₂)₀₋₄OR°, —O—(CH₂)₀₋₄C(O)OR°; —(CH₂)₀₋₄CH(OR°)₂;—(CH₂)₀₋₄SR°; —(CH₂)₀₋₄Ph, which may be substituted with R°;—(CH₂)₀₋₄O(CH₂)₀₋₁Ph which may be substituted with R°; —CH═CHPh, whichmay be substituted with R°; —(CH₂)₀₋₄O(CH₂)₀₋₁-pyridyl which may besubstituted with R°; —NO₂; —CN; —N₃; —(CH₂)₀₋₄N(R°)₂;—(CH₂)₀₋₄N(R°)C(O)R°; —N(R°)C(S)R°; —(CH₂)₀₋ ₄N(R°)C(O)NR°₂;—N(R°)C(S)NR°₂; —(CH₂)₀₋₄N(R°)C(O)OR°; —N(R°)N(R°)C(O)R°;—N(R°)N(R°)C(O)NR°₂; —N(R°)N(R°)C(O)OR°; —(CH₂)₀₋₄C(O)R°; —C(S)R°;—(CH₂)₀₋₄C(O)OR°; —(CH₂)₀₋₄C(O)SR°; —(CH₂)₀₋₄C(O)OSiR°₃;—(CH₂)₀₋₄OC(O)R°; —OC(O)(CH₂)₀₋₄SR°; —(CH₂)₀₋₄SC(O)R°;—(CH₂)₀₋₄C(O)NR°₂; —C(S)NR°₂; —C(S)SR°; —SC(S)SR°, —(CH₂)₀₋₄0C(O)NR°₂;—C(O)N(OR°)R°; —C(O)C(O)R°; —C(O)CH₂C(O)R°; —C(NOR°)R°; —(CH₂)₀₋₄SSR°;—(CH₂)₀₋₄S(O)₂R°; —(CH₂)₀₋₄S(O)(NH)R°; —(CH₂)₀₋₄S(O)₂OR°;—(CH₂)₀₋₄OS(O)₂R°; —S(O)₂NR°₂; —(CH₂)₀₋₄S(O)R°; —N(R°)S(O)₂NR°₂;—N(R°)S(O)₂R°; —N(OR°)R°; —C(NH)NR°₂; —P(O)₂R°; —P(O)R°₂; —OP(O)R°₂;—OP(O)(OR°)₂; SiR°₃; -(C₁₋₄ straight or branched alkylene)O—N(R°)₂; or-(C₁₋₄ straight or branched alkylene)C(O)O—N(R°)₂, wherein each R° maybe substituted as defined below and is independently hydrogen, C₁₋₆aliphatic, —CH₂Ph, —O(CH₂)₀₋₁Ph, —CH₂—(5- to 6-membered heteroarylring), a 5- to 6-membered saturated, partially unsaturated, or aryl ringhaving 0-4 heteroatoms independently selected from nitrogen, oxygen, orsulfur, or an 8- to 10-membered bicyclic aryl ring having 0-4heteroatoms independently selected from nitrogen, oxygen, or sulfur, or,notwithstanding the definition above, two independent occurrences of R°,taken together with their intervening atom(s), form a 3- to 12-memberedsaturated, partially unsaturated, or aryl mono- or bicyclic ring having0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur,which may be substituted as defined below.

Suitable monovalent substituents on R° (or the ring formed by taking twoindependent occurrences of R° together with their intervening atoms),are independently halogen, —(CH₂)₀₋₂R^(•), -(haloR^(•)), —(CH₂)₀₋₂OH,—(CH₂)₀₋₂OR^(•), —(CH₂)₀₋₂CH(OR^(•))₂; -O(haloR^(•)), —CN, —N₃,—(CH₂)₀₋₂C(O)R^(•), —(CH₂)₀₋₂C(O)OH, —(CH₂)₀₋₂C(O)OR^(•),—(CH₂)₀₋₂SR^(•), —(CH₂)₀₋₂SH, —(CH₂)₀₋₂NH₂, —(CH₂)₀₋₂NHR^(•),—(CH₂)₀₋₂NR^(•) ₂, —NO₂, —SiR^(•) ₃, —OSiR^(•) ₃, —C(O)SR^(•), -(C₁₋₄straight or branched alkylene)C(O)OR^(•), or —SSR^(•) wherein each R^(•)is unsubstituted or where preceded by “halo” is substituted only withone or more halogens, and is independently selected from C₁₋ ₄aliphatic, —CH₂Ph, —O(CH₂)₀₋₁Ph, or a 3- to 6-membered saturated,partially unsaturated, or aryl ring having 0-4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur. Suitable divalentsubstituents on a saturated carbon atom of R° include ═O and ═S.

Suitable divalent substituents on a saturated carbon atom of an“optionally substituted” group include the following: ═O (“oxo”), ═S,═NNR*₂, ═NNHC(O)R*, ═NNHC(O)OR*, ═NNHS(O)₂R*, ═NR*, ═NOR*,—O(C(R*₂))₂₋₃O—, or —S(C(R*₂))₂₋₃S—, wherein each independent occurrenceof R* is selected from hydrogen, C₁₋₆ aliphatic which may be substitutedas defined below, or an unsubstituted 5- to 6-membered saturated,partially unsaturated, or aryl ring having 0-4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur. Suitable divalentsubstituents that are bound to vicinal substitutable carbons of an“optionally substituted” group include: —O(CR*₂)₂₋₃O—, wherein eachindependent occurrence of R* is selected from hydrogen, C₁₋₆ aliphaticwhich may be substituted as defined below, or an unsubstituted5-6-membered saturated, partially unsaturated, or aryl ring having 0-4heteroatoms independently selected from nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R* include halogen,—R^(•), -(haloR^(•)), —OH, —OR^(•), —O(haloR^(•)), —CN, —C(O)OH,—C(O)OR^(•), —NH₂, —NHR^(•), —NR^(•) ₂, or —NO₂, wherein each R^(•) isunsubstituted or where preceded by “halo” is substituted only with oneor more halogens, and is independently C₁₋₄ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, or a 5- to 6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

Suitable substituents on a substitutable nitrogen of an “optionallysubstituted” group include R^(†)’, -NR^(†) ₂, —C(O)R^(†), —C(O)OR^(†),—C(O)C(O)R^(†), —C(O)CH₂C(O)R^(†), —S(O)₂R^(†), —S(O)₂NR^(†) ₂,—C(S)NR^(t) ₂, —C(NH)NR^(t) ₂, or —N(R^(†))S(O)₂R^(†); wherein eachR^(†) is independently hydrogen, C₁₋₆ aliphatic which may be substitutedas defined below, unsubstituted —OPh, or an unsubstituted 5- to6-membered saturated, partially unsaturated, or aryl ring having 0-4heteroatoms independently selected from nitrogen, oxygen, or sulfur, or,notwithstanding the definition above, two independent occurrences ofR^(†), taken together with their intervening atom(s) form anunsubstituted 3- to 12-membered saturated, partially unsaturated, oraryl mono- or bicyclic ring having 0-4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R^(†) are independentlyhalogen, —R^(•), -(haloR^(•)), —OH, —OR^(•), -O(haloR^(•)), —CN,—C(O)OH, —C(O)OR^(•), —NH₂, —NHR^(•), —NR^(•) ₂, or —NO₂, wherein eachR^(•) is unsubstituted or where preceded by “halo” is substituted onlywith one or more halogens, and is independently C₁₋₄ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, or a 5- to 6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

Therapeutic agent: As used herein, the phrase “therapeutic agent” ingeneral refers to any agent that elicits a desired pharmacologicaleffect when administered to an organism. In some embodiments, an agentis considered to be a therapeutic agent if it demonstrates astatistically significant effect across an appropriate population. Insome embodiments, the appropriate population may be a population ofmodel organisms. In some embodiments, an appropriate population may bedefined by various criteria, such as a certain age group, gender,genetic background, preexisting clinical conditions, etc. In someembodiments, a therapeutic agent is a substance that can be used toalleviate, ameliorate, relieve, inhibit, prevent, delay onset of, reduceseverity of, and/or reduce incidence of one or more symptoms or featuresof a disease, disorder, and/or condition. In some embodiments, a“therapeutic agent” is an agent that has been or is required to beapproved by a government agency before it can be marketed foradministration to humans. In some embodiments, a “therapeutic agent” isan agent for which a medical prescription is required for administrationto humans.

Treat: As used herein, the terms “treat,” “treatment,” or “treating”refer to any method used to partially or completely alleviate,ameliorate, relieve, inhibit, prevent, delay onset of, reduce severityof, and/or reduce incidence of one or more symptoms or features of adisease, disorder, and/or condition. Treatment may be administered to asubject who does not exhibit signs of a disease, disorder, and/orcondition. In some embodiments, treatment may be administered to asubject who exhibits only early signs of the disease, disorder, and/orcondition, for example, for the purpose of decreasing the risk ofdeveloping pathology associated with the disease, disorder, and/orcondition.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS Programmed AxonalDeseneration and SARM1

Axonal degeneration is a major pathological feature of neurologicaldiseases such as, but not limited to, Alzheimer’s disease, Parkinson’sdisease, ALS, multiple sclerosis, diabetic peripheral neuropathy,chemotherapy-induced peripheral neuropathy, inherited neuropathy,traumatic brain injury, and/or glaucoma. Damaged or unhealthy axons areeliminated via an intrinsic self-destruction program that is distinctfrom traditional cellular death pathways like apoptosis known asWallerian degeneration. (Gerdts, J., et al., Neuron, 2016, 89, 449-460;Whitmore, A.V. et al., Cell Death Differ., 2003, 10, 260-261). InWallerian degeneration, a peripheral nerve undergoes selective breakdownof the axon segment distal to an injury, whereas the proximal axonsegment and cell body remain intact. This degeneration is characterized,first, by a depletion of nicotinamide mononucleotide adenyltransferase(NMNAT), followed by nicotinamide adenine dinucleotide (NAD+) loss,adenosine tri-phosphate (ATP) loss, neurofilament proteolysis, andfinally axonal degradation approximately 8 to 24 hours following injury.(Gerdts, J., et al., Neuron, 2016, 89, 449-460).

NAD+ is a ubiquitous metabolite with critical roles in energy metabolismand cell signaling (Belenkey et al., Trends Biochem., 2007, 32, 12-19;Chiarugi et al., Nat. Rev. Cancer, 2012, 12, 741-752). The homeostaticregulation of NAD+ levels is also responsible for maintaining axonalstability and integrity. Accordingly, manipulations that increase axonallocalization of NMNAT1 confer axonal protection (Babetto et al., CellRep., 2010, 3, 1422-1429; Sasaki et al., J. Neurosci., 2009).

In a genome-wide RNAi screen in primary mouse neurons, Sterile Alpha andTIR motif-containing 1 (SARM1) was identified, in which knockdown ofSARM1 led to long-lasting protection of sensory neurons againstinjury-induced axon degeneration (Gerdts et al., J Neurosci, 2013, 33,13569-13580). SARM1 belongs to the family of cytosolic adaptor proteins,but is unique among its members because it is the most evolutionaryancient adaptor, paradoxically inhibits TLR signaling, and has beenidentified as the central executioner of the injury-induced axon deathpathway (O′Neill, L.A. & Bowie, A.G., Nat. Rev. Immunol., 2007, 7,353-364; Osterloh, J.M., et al., Science, 2012, 337, 481-484; Gerdts,J., et al., J. Neurosci. 33, 2013, 13569-13580). Activation of SARM1 viaaxonal injury or forced dimerization of SARM1-TIR domains promotes rapidand catastrophic depletion of Nicotinamide Adenine Dinucleotide (NAD+),followed soon after by axonal degradation, thus highlighting the centralrole of NAD+ homeostasis in axonal integrity. (Gerdts, J., et al.,Science, 2015, 348, 453-457). SARM1 is required for this injury-inducedNAD+ depletion both in vitro and in vivo and SARM1 activation triggersaxon degeneration locally via NAD(+) destruction (Gerdts et al., et al.,Science, 2015 348, 452-457; Sasaki et al., J. Biol. Chem. 2015, 290,17228-17238; both of which are hereby incorporated by reference in theirentireties).

From genetic loss-of-function studies it is clear that SARM1 serves asthe central executioner of the axonal degeneration pathway following aninjury. Genetic knockout of SARM1 allows for preservation of axons for14 or more days after nerve transection (Osterloh, J.M., et al.,Science, 2012, 337, 481-484; Gerdts, J., et al. J. Neurosci., 2013, 33,13569-13580) and also improves functional outcomes in mice aftertraumatic brain injury (Henninger, N. et al., Brain 139, 2016,1094-1105). In addition to the role of SARM1 in direct axonal injury,SARM1 is also required for axonal degeneration observed inchemotherapy-induced peripheral neuropathy. Loss of SARM1 blockschemotherapy-induced peripheral neuropathy, both inhibiting axonaldegeneration and heightened pain sensitivity that develops afterchemotherapeutic vincristine treatment (Geisler et al, Brain, 2016, 139,3092-3108).

SARM1 contains multiple conserved motifs including SAM domains, ARM/HEATmotifs and a TIR domain (FIG. 1 ) that mediate oligomerization andprotein-protein interactions (O′Neill, L.A. & Bowie, A.G., Nat. Rev.Immunol., 2007, 7, 353-364; Tewari, R., et al., Trends Cell Biol., 2010,20, 470-481; Qiao, F. & Bowie, J.U., Sci. STKE 2005, re7, 2005). TIRdomains are commonly found in signaling proteins functioning in innateimmunity pathways where they serve as scaffolds for protein complexes(O′Neill, L.A. & Bowie, A.G., Nat. Rev. Immunol., 2007, 7, 353-364).Interestingly, dimerization of SARM1-TIR domains is sufficient to induceaxonal degeneration and to rapidly trigger degradation of NAD+by actingas the NAD+ cleaving enzyme (Milbrandt et al., WO 2018/057989; Gerdts,J., et al., Science, 2015, 348, 453-457). Given the central role ofSARM1 in the axonal-degeneration pathway and its identified NADaseactivity, efforts have been undertaken to identify agents that canregulate SARM1, and potentially act as useful therapeutic agents, forexample, to protect against neurodegenerative diseases includingperipheral neuropathy, traumatic brain injury, and/or neurodegenerativediseases.

Among other things, the present disclosure provides certain compoundsand/or compositions that act as SARM1 inhibitory agents (e.g., as SARM1inhibitory agents), and technologies relating thereto.

Compounds

In some embodiments, the present disclosure provides a compound ofFormula I:

or a pharmaceutically acceptable salt thereof, wherein:

-   Ring A, together with the carbon atoms to which it is fused, is a    6-membered aryl ring or a 6-membered heteroaryl ring having 1-2    nitrogen atoms;-   X is selected from C—R^(x) and N;-   L is an optionally substituted C₁₋₄ aliphatic chain wherein one or    two carbon atoms in the aliphatic chain are optionally replaced by a    group independently selected from —O—, —N(R)—, —S—,    —C(O)—,—C(O)N(R)—, —N(R)C(O)—, —C(O)O—, —OC(O)—, —S(O)₂N(R)—,    —N(R)S(O)₂—, and a bivalent 3- to 5-membered monocyclic, bicyclic,    or bridged bicyclic carbocyclic ring;-   R¹ is an optionally substituted group selected from a 3- to    7-membered saturated or partially unsaturated heterocyclic ring    having 1-3 heteroatoms independently selected from oxygen, nitrogen,    and sulfur and a 5- to 6-membered heteroaryl ring having 1-3    heteroatoms independently selected from oxygen, nitrogen, and    sulfur;-   R² is hydrogen, halogen, N(R′)₂, OR′, or an optionally substituted    group selected from C₁₋₆ aliphatic, a 3- to 7-membered saturated or    partially unsaturated heterocyclic ring having 1-3 heteroatoms    independently selected from oxygen, nitrogen, and sulfur, phenyl, a    5- to 6-membered heteroaryl ring having 1-3 heteroatoms    independently selected from oxygen, nitrogen, and sulfur, a 8- to    10-membered bicyclic saturated, partially unsaturated or aryl    carbocyclic ring, a 8- to 10-membered bicyclic saturated or    partially unsaturated heterocyclic ring having 1-3 heteroatoms    independently selected from oxygen, nitrogen, and sulfur, and a 8-    to 10-membered bicyclic heteroaryl ring having 1-3 heteroatoms    independently selected from oxygen, nitrogen, and sulfur;-   R³ is independently hydrogen or an optionally substituted group    selected from C₁₋₆ aliphatic, a 3-to 7-membered saturated or    partially unsaturated heterocyclic ring having 1-3 heteroatoms    independently selected from oxygen, nitrogen, and sulfur, phenyl,    and a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms    independently selected from oxygen, nitrogen, and sulfur;-   each R^(x) and R^(y) is independently selected from hydrogen,    halogen, cyano, OR″, SR″, N(R″)₂, and optionally substituted C₁₋₄    aliphatic;-   each of R, R′, and R″ is independently hydrogen or an optionally    substituted group selected from C₁₋₆ aliphatic, a 3- to 7-membered    saturated or partially unsaturated heterocyclic ring having 1-3    heteroatoms independently selected from oxygen, nitrogen, and    sulfur, phenyl, and a 5- to 6-membered heteroaryl ring having 1-3    heteroatoms independently selected from oxygen, nitrogen, and    sulfur; or:    -   R and R², together with the intervening atom(s) to which they        are attached, form an optionally substituted 3- to 7-membered        monocyclic heterocyclic ring having 0-2 additional heteroatoms        independently selected from oxygen, nitrogen, and sulfur; or    -   two R′ groups, together with the nitrogen atom to which they are        attached, form an optionally substituted 3- to 7-membered        monocyclic heterocyclic ring having 0-2 additional heteroatoms        independently selected from oxygen, nitrogen, and sulfur; or    -   two R″ groups, together with the nitrogen atom to which they are        attached, form an optionally substituted 3- to 7-membered        monocyclic heterocyclic ring having 0-2 additional heteroatoms        independently selected from oxygen, nitrogen, and sulfur; and-   n is 0, 1, or 2.

As defined generally above, Ring A, together with the carbon atoms towhich it is fused, is a 6-membered aryl ring or a 6-membered heteroarylring having 1-2 nitrogen atoms. In some embodiments, Ring A is a6-membered aryl ring. In some embodiments, Ring A is a 6-memberedheteroaryl ring having 1-2 nitrogen atoms. In some embodiments, Ring Ais a 6-membered heteroaryl ring having 1 nitrogen atom. In someembodiments, Ring A is a 6-membered heteroaryl ring having 2 nitrogenatoms. In some such embodiments, Ring A is selected from pyrimidinyl andpyridazinyl.

In some embodiments, the present disclosure provides a compound ofFormulae I-a, I-b, I-c, I-d, I-e, I-f, and I-g:

or a pharmaceutically acceptable salt thereof, wherein each of X, L, R¹,R², R³, R^(y), and n is as defined above and described herein.

As defined generally above, X is selected from C-R^(x) and N. In someembodiments of Formulae I-a, I-b, I-c, I-d, I-e, I-f, and I-g, X isC-R^(x). Accordingly, in some embodiments, the present disclosureprovides a compound of Formulae I-a-i, I-b-i, I-c-i, I-d-i, I-e-i,I-f-i, and I-g-i:

or a pharmaceutically acceptable salt thereof, wherein each of L, R¹,R², R³, R^(x), R^(y), and n is as defined above and described herein.

In some embodiments of Formulae I-a, I-b, I-c, I-d, I-e, I-f, and I-g, Xis N. Accordingly, in some embodiments, the present disclosure providesa compound of Formulae I-a-ii, I-b-ii, I-c-ii, I-d-ii, I-e-ii, I-f-ii,and I-g-ii:

or a pharmaceutically acceptable salt thereof, wherein each of L, R¹,R², R³, R^(y), and n is as defined above and described herein.

As defined generally above, L is an optionally substituted C₁₋₄aliphatic chain wherein one or two carbon atoms in the aliphatic chainare optionally replaced by a group independently selected from —O—,—N(R)—, —S—, —C(O)—, —C(O)N(R)—, —N(R)C(O)—, —C(O)O—, —OC(O)—,—S(O)₂N(R)—, —N(R)S(O)₂—, and a bivalent 3- to 5-membered monocyclic,bicyclic, or bridged bicyclic carbocyclic ring. In some embodiments, Lis an optionally substituted C₁₋₂ aliphatic chain wherein one or twocarbon atoms in the aliphatic chain are optionally replaced by a groupindependently selected from —O—, —N(R)—, —S—, —C(O)—, —C(O)N(R)—,—N(R)C(O)—, —C(O)O—,—OC(O)—, —S(O)₂N(R)—, —N(R)S(O)₂—, and a bivalent 3-to 5-membered monocyclic, bicyclic, or bridged bicyclic carbocyclicring. In some embodiments, L is an optionally substituted C₁₋₂ aliphaticchain wherein one carbon atom in the aliphatic chain is replaced by agroup selected from —C(O)N(R)—, —N(R)C(O)—, —C(O)O—, —OC(O)—,—S(O)₂N(R)—, and —N(R)S(O)₂—. In some embodiments, L is an optionallysubstituted C₁₋₂ aliphatic chain wherein one carbon atom in thealiphatic chain is replaced by a group selected from —C(O)N(H)—,—N(H)C(O)—, —C(O)O—, —OC(O)—,—S(O)₂N(H)—, and —N(H)S(O)₂—. In someembodiments, L is an optionally substituted C₁₋₂ aliphatic chain whereinone carbon atom in the aliphatic chain is replaced by a group selectedfrom —C(O)N(R)— and —N(R)C(O)—. In some embodiments, L is an optionallysubstituted C₁₋₂ aliphatic chain wherein one carbon atom in thealiphatic chain is replaced by a group selected from —C(O)N(H)— and—N(H)C(O)—.

In some embodiments, L is an optionally substituted C₃₋₄ aliphatic chainwherein one or two carbon atoms in the aliphatic chain are optionalslyreplaced by a group independently selected from —O—, —N(R)—, —S—,—C(O)—, —C(O)N(R)—, —N(R)C(O)—, —C(O)O—, —OC(O)—,—S(O)₂N(R)—,—N(R)S(O)₂—, and a bivalent 3- to 5-membered monocyclic,bicyclic, or bridged bicyclic carbocyclic ring. In some embodiments, Lis an optionally substituted C₃₋₄ aliphatic chain wherein one or twocarbon atoms in the aliphatic chain are optionally replaced by a groupindependently selected from —O—, —N(R)—, —S—, and —C(O)—. In someembodiments, L is an optionally substituted C₃₋₄ aliphatic chain whereinone or two carbon atoms in the aliphatic chain are optionally replacedby a group independently selected from —O—, —N(H)—, —S—, and —C(O)—. Insome embodiments, L is an optionally substituted C₃₋₄ aliphatic chainwherein one carbon atom in the aliphatic chain is replaced by a groupselected from —C(O)N(R)— and —N(R)C(O)—. In some embodiments, L is anoptionally substituted C₃₋₄ aliphatic chain wherein one carbon atom inthe aliphatic chain is replaced by a group selected from —C(O)N(H)— and—N(H)C(O)—.

In some embodiments, L is an optionally substituted C₁₋₄ aliphatic chainwherein one carbon atom in the aliphatic chain is replaced by —C(O)—,and one additional carbon atom is optionally replaced by a groupselected from —O—, —N(R)—, —S—, —C(O)N(R)—, —N(R)C(O)—, —C(O)O—,—OC(O)—,—S(O)₂N(R)—, —N(R)S(O)₂—, and a bivalent 3- to 5-membered monocyclic,bicyclic, or bridged bicyclic carbocyclic ring.

In some embodiments, L is an optionally substituted C₁₋₄ aliphatic chainwherein one carbon atom in the aliphatic chain is replaced by —C(O)—,and one additional carbon atom is optionally replaced by a groupselected from —O—, —N(R)—, —S—, and a bivalent 3- to 5-memberedmonocyclic, bicyclic, or bridged bicyclic carbocyclic ring. In someembodiments, L is an optionally substituted C₁₋₄ aliphatic chain whereinone carbon atom in the aliphatic chain is replaced by —C(O)—, and oneadditional carbon atom is optionally replaced by a group selected from—O—, —N(H)—, —S—, and a bivalent 3- to 5-membered monocyclic, bicyclic,or bridged bicyclic carbocyclic ring.

In some embodiments, L is an optionally substituted C₃₋₄ aliphatic chainwherein one carbon atom in the aliphatic chain is replaced by —C(O)—,and one additional carbon atom is optionally replaced by a groupselected from —O—, -N(R)-, —S—, and a bivalent 3- to 5-memberedmonocyclic, bicyclic, or bridged bicyclic carbocyclic ring. In someembodiments, L is an optionally substituted C₃₋₄ aliphatic chain whereinone carbon atom in the aliphatic chain is replaced by —C(O)—, and oneadditional carbon atom is optionally replaced by a group selected from—O—, —N(H)—, —S—, and a bivalent 3- to 5-membered monocyclic, bicyclic,or bridged bicyclic carbocyclic ring.

In some embodiments, L is an optionally substituted C₁₋₄ aliphatic chainwherein two carbon atoms in the aliphatic chain are replaced by —N(R)—and —C(O)—.

In some embodiments, L is an optionally substituted C₁₋₄ aliphatic chainwherein at least one carbon atom in the aliphatic chain is replaced by—C(O)N(R)—. In some such embodiments, L is selected from

In some embodiments, L is selected from

As defined generally above, R¹ is an optionally substituted groupselected from a 3- to 7-membered saturated or partially unsaturatedheterocyclic ring having 1-3 heteroatoms independently selected fromoxygen, nitrogen, and sulfur and a 5- to 6-membered heteroaryl ringhaving 1-3 heteroatoms independently selected from oxygen, nitrogen, andsulfur.

In some embodiments, R¹ is an optionally substituted 3- to 7-memberedsaturated or partially unsaturated heterocyclic ring having 1-3heteroatoms independently selected from oxygen, nitrogen, and sulfur. Insome embodiments, R¹ is an optionally substituted 5- to 6-memberedsaturated or partially unsaturated heterocyclic ring having 1-3heteroatoms independently selected from oxygen, nitrogen, and sulfur. Insome embodiments, R¹ is an optionally substituted group selected frompyrrolidinyl, piperidinyl, morpholinyl, and piperazinyl.

In some embodiments, R¹ is an optionally substituted 5- to 6-memberedheteroaryl ring having 1-3 heteroatoms independently selected fromoxygen, nitrogen, and sulfur.

In some embodiments, R¹ is an optionally substituted 5-memberedheteroaryl ring having 1-3 heteroatoms independently selected fromoxygen, nitrogen, and sulfur. In some embodiments, R¹ is an optionallysubstituted 5-membered heteroaryl ring having 1-2 heteroatomsindependently selected from oxygen, nitrogen, and sulfur. In someembodiments, R¹ is an optionally substituted group selected frompyrazolyl, imidazolyl, isothiazolyl, thiazolyl, oxazolyl, and thiophenylring.

In some embodiments, R¹ is an optionally substituted 6-memberedheteroaryl ring having 1-3 nitrogen atoms. In some embodiments, R¹ is anoptionally substituted 6-membered heteroaryl ring having 1-2 nitrogenatoms. In some embodiments, R¹ is an optionally substituted groupselected from pyridinyl, pyrimidinyl and pyridazinyl.

In some embodiments, R¹ is selected from

In certain particularly preferred embodiments, R¹ is selected from

As defined generally above, R² is hydrogen, halogen, N(R′)₂, OR′, or anoptionally substituted group selected from C₁₋₆ aliphatic, a 3- to7-membered saturated or partially unsaturated heterocyclic ring having1-3 heteroatoms independently selected from oxygen, nitrogen, andsulfur, phenyl, a 5- to 6-membered heteroaryl ring having 1-3heteroatoms independently selected from oxygen, nitrogen, and sulfur, a8- to 10-membered bicyclic saturated, partially unsaturated or arylcarbocyclic ring, a 8- to 10-membered bicyclic saturated or partiallyunsaturated heterocyclic ring having 1-3 heteroatoms independentlyselected from oxygen, nitrogen, and sulfur, and a 8- to 10-memberedbicyclic heteroaryl ring having 1-3 heteroatoms independently selectedfrom oxygen, nitrogen, and sulfur.

In some embodiments, R² is hydrogen. In some embodiments, R² is halogen,N(R′)₂, OR′, or an optionally substituted group selected from C₁₋₆aliphatic, a 3- to 7-membered saturated or partially unsaturatedheterocyclic ring having 1-3 heteroatoms independently selected fromoxygen, nitrogen, and sulfur, phenyl, a 5- to 6-membered heteroaryl ringhaving 1-3 heteroatoms independently selected from oxygen, nitrogen, andsulfur, a 8- to 10-membered bicyclic saturated, partially unsaturated oraryl carbocyclic ring, a 8- to 10-membered bicyclic saturated orpartially unsaturated heterocyclic ring having 1-3 heteroatomsindependently selected from oxygen, nitrogen, and sulfur, and a 8- to10-membered bicyclic heteroaryl ring having 1-3 heteroatomsindependently selected from oxygen, nitrogen, and sulfur.

In some embodiments, R² is halogen. In some embodiments, R² is N(R′)₂.In some such embodiments, R² is NH₂. In some embodiments, R² is OR′. Insome such embodiments, R² is OH.

In some embodiments, R² is optionally substituted C₁₋₆ aliphatic. Insome such embodiments, R² is an optionally substituted group selectedfrom cyclopentyl or cyclohexyl. In some embodiments, R² is C₁₋₆aliphatic. In some embodiments, R² is methyl. In some embodiments, R² isethyl. In some embodiments, R² is cyclohexyl.

In some embodiments, R² is optionally substituted phenyl.

In some embodiments, R² is an optionally substituted 3- to 7-memberedsaturated or partially unsaturated heterocyclic ring having 1-3heteroatoms independently selected from oxygen, nitrogen, and sulfur. Insome embodiments, R² is an optionally substituted 3-membered saturatedheterocyclic ring having 1 heteroatom selected from oxygen, nitrogen,and sulfur. In some embodiments, R² is an optionally substituted4-membered saturated heterocyclic ring having 1 heteroatom selected fromoxygen, nitrogen, and sulfur. In some embodiments, R² is an optionallysubstituted 5-membered saturated or partially unsaturated heterocyclicring having 1-2 heteroatoms independently selected from oxygen,nitrogen, and sulfur. In some embodiments, R² is an optionallysubstituted 6-membered saturated or partially unsaturated heterocyclicring having 1-3 heteroatoms independently selected from oxygen,nitrogen, and sulfur. In some embodiments, R² is an optionallysubstituted group selected from pyrrolidinyl, piperidinyl, morpholinyl,and piperazinyl.

In some embodiments, R² is an optionally substituted 5- to 6-memberedheteroaryl ring having 1-3 heteroatoms independently selected fromoxygen, nitrogen, and sulfur. In some embodiments, R² is an optionallysubstituted 5-membered heteroaryl ring having 1-3 heteroatomsindependently selected from oxygen, nitrogen, and sulfur. In someembodiments, R² is an optionally substituted 5-membered heteroaryl ringhaving 1-2 heteroatoms independently selected from oxygen, nitrogen, andsulfur. In some such embodiments, R² is an optionally substituted groupselected from thiophenyl, pyrazolyl, and imidazolyl.

In some embodiments, R² is an optionally substituted 6-memberedheteroaryl ring having 1-3 nitrogen atoms. In some embodiments, R² is anoptionally substituted 6-membered heteroaryl ring having 1-2 nitrogenatoms. In some such embodiments, R² is an optionally substituted groupselected from pyridinyl and pyrimidinyl.

In some embodiments, R² is an optionally substituted 8- to 10-memberedbicyclic saturated, partially unsaturated or aryl carbocyclic ring. Insome embodiments, R² is an optionally substituted 9-membered bicyclicsaturated, partially unsaturated or aryl carbocyclic ring. In some suchembodiments, R² is optionally substituted 2,3-dihydro-1H-indenyl. Insome embodiments, R² is an optionally substituted 10-membered bicyclicsaturated, partially unsaturated or aryl carbocyclic ring. In some suchembodiments, R² is an optionally substituted group selected from1,2,3,4-tetrahydronaphthalenyl and naphthalenyl.

In some embodiments, R² is an optionally substituted 8- to 10-memberedbicyclic saturated or partially unsaturated heterocyclic ring having 1-3heteroatoms independently selected from oxygen, nitrogen, and sulfur. Insome embodiments, R² is an optionally substituted 9-membered bicyclicsaturated or partially unsaturated heterocyclic ring having 1-3heteroatoms independently selected from oxygen, nitrogen, and sulfur. Insome embodiments, R² is an optionally substituted 10-membered bicyclicsaturated or partially unsaturated heterocyclic ring having 1-3heteroatoms independently selected from oxygen, nitrogen, and sulfur. Insome such embodiments, R² is an optionally substituted group selectedfrom chromanyl, isochromanyl, 1,2,3,4-tetrahydroquinolinyl,3,4-dihydro-2H-benzo[b][1,4]oxazinyl, and2H-benzo[b][1,4]oxazin-3(4H)-onyl.

In some embodiments, R² is an optionally substituted 8- to 10-memberedbicyclic heteroaryl ring having 1-3 heteroatoms independently selectedfrom oxygen, nitrogen, and sulfur. In some embodiments, R² is anoptionally substituted 9-membered bicyclic heteroaryl ring having 1-3heteroatoms independently selected from oxygen, nitrogen, and sulfur. Insome such embodiments, R² is an optionally substituted group selectedfrom indolyl, benzopyrazolyl, benzimidazolyl, andimidazo[1,2-a]pyridinyl.

In some embodiments, R² is selected from the group consisting of

As defined generally above, R³ is independently hydrogen or anoptionally substituted group selected from C₁₋₆ aliphatic, a 3- to7-membered saturated or partially unsaturated heterocyclic ring having1-3 heteroatoms independently selected from oxygen, nitrogen, andsulfur, phenyl, and a 5- to 6-membered heteroaryl ring having 1-3heteroatoms independently selected from oxygen, nitrogen, and sulfur. Insome embodiments, R³ is hydrogen. In some embodiments, R³ is anoptionally substituted group selected from C₁₋₆ aliphatic, a 3- to7-membered saturated or partially unsaturated heterocyclic ring having1-3 heteroatoms independently selected from oxygen, nitrogen, andsulfur, phenyl, and a 5- to 6-membered heteroaryl ring having 1-3heteroatoms independently selected from oxygen, nitrogen, and sulfur. Insome embodiments, R³ is optionally substituted C₁₋₆ aliphatic. In someembodiments, R³ is methyl, ethyl, or isopropyl.

As defined generally above, R^(x) is selected from hydrogen, halogen,cyano, OR″, SR″, N(R″)₂, and optionally substituted C₁₋₄ aliphatic. Insome embodiments of Formulae I-a-i, I-b-i, I-c-i, I-d-ii I-e-i, I-f-i,and I-g-i, R^(x) is hydrogen. Accordingly, in some embodiments, thepresent disclosure provides a compound of Formulae I-a-iii, I-b-iii,I-c-iii, I-d-iii, I-e-iii, I-f-iii, and I-g-iii:

or a pharmaceutically acceptable salt thereof, wherein each of L, R¹,R², R³, R^(y), and n is as defined above and described herein.

In some embodiments, R^(x) is halogen, cyano, OR″, SR″, N(R″)₂, andoptionally substituted C₁₋₄ aliphatic.

In some embodiments, R^(x) is halogen. In some such embodiments, R^(x)is chloro or bromo.

In some embodiments, R^(x) is cyano.

In some embodiments, R^(x) is OR″. In some embodiments, R^(x) is OR″,wherein R″ is selected from hydrogen and optionally substituted C₁₋₆aliphatic. In some embodiments, R^(x) is OR″, wherein R” is selectedfrom hydrogen and optionally substituted C₁₋₄ aliphatic. In someembodiments, R^(x) is selected from OH, OCH₃, and OCH₂CH₃.

In some embodiments, R^(x) is SR″. In some embodiments, R^(x) is SR″,wherein R″ is selected from hydrogen and optionally substituted C₁₋₆aliphatic. In some embodiments, R^(x) is SR″, wherein R″ is selectedfrom hydrogen and optionally substituted C₁₋₄ aliphatic. In someembodiments, R^(x) is selected from SH, SCH₃, and SCH₂CH₃.

In some embodiments, R^(x) is N(R″)₂. In some embodiments, R^(x) isN(R″)₂, wherein R″ is selected from hydrogen and optionally substitutedC₁₋₆ aliphatic. In some embodiments, R^(x) is N(R″)₂, wherein R″ isselected from hydrogen and optionally substituted C₁₋₄ aliphatic. Insome embodiments, R^(x) is selected from NH₂, NHCH₃, NHCH₂CH₃, N(CH₃)₂,and N(CH₂CH₃)₂.

In some embodiments, R^(x) is optionally substituted C₁₋₄ aliphatic. Insome embodiments, R^(x) is methyl, ethyl, or isopropyl. In someembodiments, R^(x) is optionally substituted C₃₋₄ aliphatic. In somesuch embodiments, R^(x) is selected from tert-butyl,

In some embodiments, R^(x) is C₁₋₄ aliphatic optionally substituted witha group selected from halogen, —(CH₂)₀₋₄R°, —(CH₂)₀₋₄OR°,—(CH₂)₀₋₄N(R°)₂, —(CH₂)₀₋₄C(O)OR°, and —(CH₂)₀₋₄C(O)NR°₂. In some suchembodiments, R° is selected from hydrogen, C₁₋₆ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, —CH₂—(5- to 6-membered heteroaryl ring), a 5- to6-membered saturated, partially unsaturated, or aryl ring having 0-4heteroatoms independently selected from nitrogen, oxygen, and sulfur,and an 8- to 10-membered bicyclic aryl ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur, or: twoindependent occurrences of R°, taken together with their interveningatom(s), form a 3- to 12-membered saturated, partially unsaturated, oraryl mono- or bicyclic ring having 0-4 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur.

In some embodiments, R^(x) is C₁₋₄ aliphatic optionally substituted witha group selected from halogen, —R°, —OR°, —N(R°)₂, —C(O)OR°, and—C(O)NR°₂. In some embodiments, R^(x) is C₁₋₄ aliphatic optionallysubstituted with halogen. In some such embodiments, R^(x) is selectedfrom —CH₃, —CF₃, —CHF₂, and CH₂F.

In some embodiments, R^(x) is selected from —CH₂R°, —CH₂OR°, —CH₂N(R°)₂,—CH₂C(O)OR°, and —CH₂C(O)N(R°)₂. In some such embodiments, R^(x) isselected from —CH₂OH, —CH₂OCH₃, —CH₂C(O)NH₂, —CH₂C(O)NHCH₃, and—CH₂C(O)N(CH₃)₂.

As defined generally above, R^(y) is selected from hydrogen, halogen,cyano, OR″, SR″, N(R″)₂, and optionally substituted C₁₋₄ aliphatic. Insome embodiments, R^(y) is hydrogen.

In some embodiments, R^(y) is halogen, cyano, OR″, SR″, N(R″)₂, andoptionally substituted C₁₋₄ aliphatic.

In some embodiments, R^(y) is halogen. In some such embodiments, R^(y)is chloro or bromo.

In some embodiments, R^(y) is cyano.

In some embodiments, R^(y) is OR″. In some embodiments, R^(y) is OR″,wherein R″ is selected from hydrogen and optionally substituted C₁₋₆aliphatic. In some embodiments, R^(y) is OR″, wherein R″ is selectedfrom hydrogen and optionally substituted C₁₋₄ aliphatic. In someembodiments, R^(y) is selected from OH, OCH₃, and OCH₂CH₃.

In some embodiments, R^(y) is SR″. In some embodiments, R^(y) is SR″,wherein R″ is selected from hydrogen and optionally substituted C₁₋₆aliphatic. In some embodiments, R^(y) is SR″, wherein R″ is selectedfrom hydrogen and optionally substituted C₁₋₄ aliphatic. In someembodiments, R^(y) is selected from SH, SCH₃, and SCH₂CH₃.

In some embodiments, R^(y) is N(R″)₂. In some embodiments, R^(y) isN(R″)₂, wherein R″ is selected from hydrogen and optionally substitutedC₁₋₆ aliphatic. In some embodiments, R^(y) is N(R″)₂, wherein R″ isselected from hydrogen and optionally substituted C₁₋₄ aliphatic. Insome embodiments, R^(y) is selected from NH₂, NHCH₃, NHCH₂CH₃, N(CH₃)₂,and N(CH₂CH₃)₂.

In some embodiments, R^(y) is optionally substituted C₁₋₄ aliphatic. Insome embodiments, R^(y) is methyl, ethyl, or isopropyl. In someembodiments, R^(y) is optionally substituted C₃₋₄ aliphatic. In somesuch embodiments, R^(y) is selected from tert-butyl,

In some embodiments, R^(y) is C₁₋₄ aliphatic optionally substituted witha group selected from halogen, —(CH₂)₀₋₄R°, —(CH₂)₀₋₄OR°,—(CH₂)₀₋₄N(R°)₂, —(CH₂)₀₋₄C(O)OR°, and —(CH₂)₀₋₄C(O)NR°₂. In some suchembodiments, R° is selected from hydrogen, C₁₋₆ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, —CH₂—(5- to 6-membered heteroaryl ring), a 5- to6-membered saturated, partially unsaturated, or aryl ring having 0-4heteroatoms independently selected from nitrogen, oxygen, and sulfur,and an 8- to 10-membered bicyclic aryl ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur, or: twoindependent occurrences of R°, taken together with their interveningatom(s), form a 3- to 12-membered saturated, partially unsaturated, oraryl mono- or bicyclic ring having 0-4 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur.

In some embodiments, R^(y) is C₁₋₄ aliphatic optionally substituted witha group selected from halogen, —R°, —OR°, —N(R°)₂, —C(O)OR°, and—C(O)NR°₂. In some embodiments, R^(y) is C₁₋₄ aliphatic optionallysubstituted with halogen. In some such embodiments, R^(y) is selectedfrom —CH₃, —CF₃, —CHF₂, and CH₂F.

In some embodiments, R^(y) is selected from —CH₂R°, —CH₂OR°, —CH₂N(R°)₂,—CH₂C(O)OR°, and —CH₂C(O)N(R°)₂. In some such embodiments, R^(y) isselected from —CH₂OH, —CH₂OCH₃, —CH₂C(O)NH₂, —CH₂C(O)NHCH₃, and—CH₂C(O)N(CH₃)₂.

As defined generally above, R is hydrogen or an optionally substitutedgroup selected from C₁₋₆ aliphatic, a 3- to 7-membered saturated orpartially unsaturated heterocyclic ring having 1-3 heteroatomsindependently selected from oxygen, nitrogen, and sulfur, phenyl, and a5- to 6-membered heteroaryl ring having 1-3 heteroatoms independentlyselected from oxygen, nitrogen, and sulfur; or R and R², together withthe intervening atom(s) to which they are attached, form an optionallysubstituted 3- to 7-membered monocyclic heterocyclic ring having 0-2additional heteroatoms independently selected from oxygen, nitrogen, andsulfur. In some embodiments, R is hydrogen. In some embodiments, R is anoptionally substituted group selected from C₁₋₆ aliphatic, a 3- to7-membered saturated or partially unsaturated heterocyclic ring having1-3 heteroatoms independently selected from oxygen, nitrogen, andsulfur, phenyl, and a 5- to 6-membered heteroaryl ring having 1-3heteroatoms independently selected from oxygen, nitrogen, and sulfur; orR and R², together with the intervening atom(s) to which they areattached, form an optionally substituted 3- to 7-membered monocyclicheterocyclic ring having 0-2 additional heteroatoms independentlyselected from oxygen, nitrogen, and sulfur.

In some embodiments, R is optionally substituted C₁₋₆ aliphatic. In someembodiments, R is C₁₋₆ aliphatic optionally substituted with oxo andOR°, wherein R° is C₁₋₆ aliphatic. In some such embodiments, R is—C(O)OtBu.

In some embodiments, R is C₁₋₆ aliphatic. In some such embodiments, R ismethyl or ethyl.

In some embodiments, R is selected from hydrogen and optionallysubstituted C₁₋₆ aliphatic. In some such embodiments, R is selected fromhydrogen, methyl and ethyl.

As defined generally above, R′ is hydrogen or an optionally substitutedgroup selected from C₁₋₆ aliphatic, a 3- to 7-membered saturated orpartially unsaturated heterocyclic ring having 1-3 heteroatomsindependently selected from oxygen, nitrogen, and sulfur, phenyl, and a5- to 6-membered heteroaryl ring having 1-3 heteroatoms independentlyselected from oxygen, nitrogen, and sulfur; or two R′ groups, togetherwith the nitrogen atom to which they are attached, form an optionallysubstituted 3- to 7-membered monocyclic heterocyclic ring having 0-2additional heteroatoms independently selected from oxygen, nitrogen, andsulfur. In some embodiments, R′ is hydrogen. In some embodiments, R′ isan optionally substituted group selected from C₁₋₆ aliphatic, a 3- to7-membered saturated or partially unsaturated heterocyclic ring having1-3 heteroatoms independently selected from oxygen, nitrogen, andsulfur, phenyl, and a 5- to 6-membered heteroaryl ring having 1-3heteroatoms independently selected from oxygen, nitrogen, and sulfur; ortwo R′ groups, together with the nitrogen atom to which they areattached, form an optionally substituted 3- to 7-membered monocyclicheterocyclic ring having 0-2 additional heteroatoms independentlyselected from oxygen, nitrogen, and sulfur.

In some embodiments, R′ is optionally substituted C₁₋₆ aliphatic. Insome embodiments, R′ is C₁₋₆ aliphatic optionally substituted with oxoand OR°, wherein R° is C₁₋₆ aliphatic. In some such embodiments, R′ is—C(O)OtBu.

In some embodiments, R′ is selected from hydrogen and —C(O)OtBu.

In some embodiments, R′ is C₁₋₆ aliphatic. In some such embodiments, R′is methyl or ethyl.

In some embodiments, R′ is selected from hydrogen and optionallysubstituted C₁₋ ₆ aliphatic. In some such embodiments, R′ is selectedfrom hydrogen, methyl and ethyl.

As defined generally above, R″ is hydrogen or an optionally substitutedgroup selected from C₁₋₆ aliphatic, a 3- to 7-membered saturated orpartially unsaturated heterocyclic ring having 1-3 heteroatomsindependently selected from oxygen, nitrogen, and sulfur, phenyl, and a5- to 6-membered heteroaryl ring having 1-3 heteroatoms independentlyselected from oxygen, nitrogen, and sulfur; or two R″ groups, togetherwith the nitrogen atom to which they are attached, form an optionallysubstituted 3- to 7-membered monocyclic heterocyclic ring having 0-2additional heteroatoms independently selected from oxygen, nitrogen, andsulfur. In some embodiments, R″ is hydrogen. In some embodiments, R″ isan optionally substituted group selected from C₁₋₆ aliphatic, a 3- to7-membered saturated or partially unsaturated heterocyclic ring having1-3 heteroatoms independently selected from oxygen, nitrogen, andsulfur, phenyl, and a 5- to 6-membered heteroaryl ring having 1-3heteroatoms independently selected from oxygen, nitrogen, and sulfur; ortwo R″ groups, together with the nitrogen atom to which they areattached, form an optionally substituted 3- to 7-membered monocyclicheterocyclic ring having 0-2 additional heteroatoms independentlyselected from oxygen, nitrogen, and sulfur.

In some embodiments, R″ is optionally substituted C₁₋₆ aliphatic. Insome embodiments, R″ is C₁₋₆ aliphatic optionally substituted with oxoand OR°, wherein R° is C₁₋₆ aliphatic. In some such embodiments, R″ is—C(O)OtBu.

In some embodiments, R″ is selected from hydrogen and —C(O)OtBu.

In some embodiments, R″ is C₁₋₆ aliphatic. In some such embodiments, R″is methyl or ethyl.

In some embodiments, R″ is selected from hydrogen and optionallysubstituted C₁₋ ₆ aliphatic. In some such embodiments, R″ is selectedfrom hydrogen, methyl and ethyl.

In some embodiments of Formulae I-a, I-a-i, I-a-ii, I-a-iii, I-b, I-b-i,I-b-ii, I-b-iii, I-c, I-c-i, I-c-ii, I-c-iii, I-d, I-d-i, I-d-ii,I-d-iii, I-e, I-e-i, I-e-ii, I-e-iii, I-f, I-f-i, I-f-ii, I-f-iii, I-g,I-g-i, I-g-ii, and I-g-iii, R³ is H. Accordingly, in some embodiments,the present disclosure provides a compound of Formulae I-a-iv, I-a-v,I-a-vi, I-a-vii, I-b-iv, I-b-v, I-b-vi, I-b-vii, I-c-iv, I-c-v, I-c-vi,I-c-vii, I-d-iv, I-d-v, I-d-vi, I-d-vii, I-e-iv, I-e-v, I-e-vi, I-e-vii,I-f-iv, I-f-v, I-f-vi, I-f-vii, I-g-iv, I-g-v, I-g-vi, and I-g-vii:

or a pharmaceutically acceptable salt thereof, wherein each of X, L, R¹,R², R^(x), R^(y), and n is as defined above and described herein.

In some embodiments, the present disclosure provides a compound ofFormulae I-a-viii, I-a-ix, I-a-x, I-a-xi, I-b-viii, I-b-ix, I-b-x,I-b-xi, I-c-viii, I-c-ix, I-c-x, I-c-xi, I-d-viii, I-d-ix, I-d-x,I-d-xi, I-e-viii, I-e-ix, I-e-x, I-e-xi, I-f-viii, I-f-ix, I-f-x,I-f-xi, I-g-viii, I-g-ix, I-g-x, and I-g-xi:

or a pharmaceutically acceptable salt thereof, wherein each of X, L, R¹,R², R³, R^(x), R^(y), and n is as defined above and described herein.

In some embodiments of Formulae I-a-viii, I-a-ix, I-a-x, I-a-xi,I-b-viii, I-b-ix, I-b-x, I-b-xi, I-c-viii, I-c-ix, I-c-x, I-c-xi,I-d-viii, I-d-ix, I-d-x, I-d-xi, I-e-viii, I-e-ix, I-e-x, I-e-xi,I-f-viii, I-f-ix, I-f-x, I-f-xi, I-g-viii, I-g-ix, I-g-x, and I-g-xi, R³is hydrogen. Accordingly, in some embodiments, the present disclosureprovides a compound of Formulae I-a-xii, I-a-xiii, I-a-xiv, I-a-xv,I-b-xii, I-b-xiii, I-b-xiv, I-b-xv, I-c-xii, I-c-xiii, I-c-xiv, I-c-xv,I-d-xii, I-d-xiii, I-d-xiv, I-d-xv, I-e-xii, I-e-xiii, I-e-xiv, I-e-xv,I-f-xii, I-f-xiii, I-f-xiv, I-f-xv, I-g-xii, I-g-xiii, I-g-xiv, andI-g-xv:

or a pharmaceutically acceptable salt thereof, wherein each of X, L, R¹,R², R^(x), R^(y), and n is as defined above and described herein.

In some embodiments, provided compounds have the structure of FormulaII:

or a pharmaceutically acceptable salt thereof, wherein:

-   R¹ is a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms    independently selected from oxygen, nitrogen, and sulfur, wherein    the 5- to 6-membered heteroaryl ring is optionally substituted with    fluorine or methyl;-   R² is a 5- to 6-membered heteroaryl ring having 1 heteroatom    selected from nitrogen and sulfur, or phenyl, wherein the 5- to    6-membered heteroaryl ring or phenyl is optionally substituted with    1-2 groups selected from fluorine and chlorine;-   R⁴ is hydrogen or methyl;-   Q is N or CH;-   X, Y and Z are independently CR⁵ or a nitrogen atom, provided that    no more than two X, Y and Z are nitrogen atoms; and-   R⁵ is hydrogen or methyl.

In a further embodiment, the compound is selected from:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the present disclosure provides a compound selectedfrom:

Example Structure Example Structure 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

or a pharmaceutically acceptable salt thereof.

In some aspects, the present disclosure provides a compound according tothe following embodiments:

Embodiment 1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

-   Ring A, together with the carbon atoms to which it is fused, is a    6-membered aryl ring or a 6-membered heteroaryl ring having 1-2    nitrogen atoms;-   X is selected from C—R^(x) and N;-   L is an optionally substituted C₁₋₄ aliphatic chain wherein one or    two carbon atoms in the aliphatic chain are optionally replaced by a    group independently selected from —O—, —N(R)—, —S—,    —C(O)—,—C(O)N(R)—, —N(R)C(O)—, —C(O)O—, —OC(O)—, —S(O)₂N(R)—,    —N(R)S(O)₂—, and a bivalent 3- to 5-membered monocyclic, bicyclic,    or bridged bicyclic carbocyclic ring;-   R¹ is an optionally substituted group selected from a 3- to    7-membered saturated or partially unsaturated heterocyclic ring    having 1-3 heteroatoms independently selected from oxygen, nitrogen,    and sulfur and a 5- to 6-membered heteroaryl ring having 1-3    heteroatoms independently selected from oxygen, nitrogen, and    sulfur;-   R² is hydrogen, halogen, N(R′)₂, OR′, or an optionally substituted    group selected from C₁₋₆ aliphatic, a 3- to 7-membered saturated or    partially unsaturated heterocyclic ring having 1-3 heteroatoms    independently selected from oxygen, nitrogen, and sulfur, phenyl, a    5- to 6-membered heteroaryl ring having 1-3 heteroatoms    independently selected from oxygen, nitrogen, and sulfur, a 8- to    10-membered bicyclic saturated, partially unsaturated or aryl    carbocyclic ring, a 8- to 10-membered bicyclic saturated or    partially unsaturated heterocyclic ring having 1-3 heteroatoms    independently selected from oxygen, nitrogen, and sulfur, and a 8-    to 10-membered bicyclic heteroaryl ring having 1-3 heteroatoms    independently selected from oxygen, nitrogen, and sulfur;-   R³ is independently hydrogen or an optionally substituted group    selected from C₁₋₆ aliphatic, a 3-to 7-membered saturated or    partially unsaturated heterocyclic ring having 1-3 heteroatoms    independently selected from oxygen, nitrogen, and sulfur, phenyl,    and a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms    independently selected from oxygen, nitrogen, and sulfur;-   each R^(x) and R^(y) is independently selected from hydrogen,    halogen, cyano, OR″, SR″, N(R″)₂, and optionally substituted C₁₋₄    aliphatic;-   each of R, R′, and R″ is independently hydrogen or an optionally    substituted group selected from C₁₋₆ aliphatic, a 3- to 7-membered    saturated or partially unsaturated heterocyclic ring having 1-3    heteroatoms independently selected from oxygen, nitrogen, and    sulfur, phenyl, and a 5- to 6-membered heteroaryl ring having 1-3    heteroatoms independently selected from oxygen, nitrogen, and    sulfur; or:    -   R and R², together with the intervening atom(s) to which they        are attached, form an optionally substituted 3- to 7-membered        monocyclic heterocyclic ring having 0-2 additional heteroatoms        independently selected from oxygen, nitrogen, and sulfur; or    -   two R′ groups, together with the nitrogen atom to which they are        attached, form an optionally substituted 3- to 7-membered        monocyclic heterocyclic ring having 0-2 additional heteroatoms        independently selected from oxygen, nitrogen, and sulfur; or    -   two R″ groups, together with the nitrogen atom to which they are        attached, form an optionally substituted 3- to 7-membered        monocyclic heterocyclic ring having 0-2 additional heteroatoms        independently selected from oxygen, nitrogen, and sulfur; and-   n is 0, 1, or 2.

Embodiment 2. The compound according to embodiment 1, wherein Ring A isa 6-membered aryl ring.

Embodiment 3. The compound according to embodiment 1, wherein Ring A isa 6-membered heteroaryl ring having 1-2 nitrogen atoms.

Embodiment 4. The compound according to embodiment 1, wherein Ring A isa 6-membered heteroaryl ring having 1 nitrogen atom.

Embodiment 5. The compound according to embodiment 1, wherein Ring A isa 6-membered heteroaryl ring having 2 nitrogen atoms.

Embodiment 6. The compound according to embodiment 1, wherein thecompound is a compound of Formulae I-a, I-b, I-c, I-d, I-e, I-f, andI-g:

or a pharmaceutically acceptable salt thereof.

Embodiment 7. The compound according to any one of embodiments 1-6,wherein X is C-R^(x).

Embodiment 8. The compound according to any one of embodiments 1-6,wherein XisN.

Embodiment 9. The compound according to embodiment 7, wherein R^(x) ishydrogen.

Embodiment 10. The compound according to embodiment 7, wherein R^(x) ishalogen.

Embodiment 11. The compound according to embodiment 7, wherein R^(x) iscyano.

Embodiment 12. The compound according to embodiment 7, wherein R^(x) isOR″.

Embodiment 13. The compound according to embodiment 7, wherein R^(x) isSR″.

Embodiment 14. The compound according to embodiment 7, wherein R^(x) isN(R″)₂.

Embodiment 15. The compound according to any one of embodiments 12-14,wherein R″ is selected from hydrogen and optionally substituted C₁₋₆aliphatic.

Embodiment 16. The compound according to embodiment 15, wherein R″ isselected from hydrogen and optionally substituted C₁₋₄ aliphatic.

Embodiment 17. The compound according to any one of embodiments 12, 15,and 16, wherein R^(x) is OH, OCH₃, and OCH₂CH₃.

Embodiment 18. The compound according to any one of embodiments 13, 15,and 16, wherein R^(x) is SH, SCH₃, and SCH₂CH₃.

Embodiment 19. The compound according to any one of embodiments 14-16,wherein R^(x) is selected from NH₂, NHCH₃, NHCH₂CH₃, N(CH₃)₂, andN(CH₂CH₃)₂.

Embodiment 20. The compound according to embodiment 7, wherein R^(x) isoptionally substituted C₁₋₄ aliphatic.

Embodiment 21. The compound according to embodiment 20, wherein R^(x) isoptionally substituted C₃₋₄ aliphatic.

Embodiment 22. The compound according to embodiment 21, wherein R^(x) isselected from tert-butyl,

Embodiment 23. The compound according to embodiment 20, wherein R^(x) isC₁₋₄ aliphatic optionally substituted with a group selected fromhalogen, —(CH₂)₀₋₄R°, —(CH₂)₀₋ ₄OR°, —(CH₂)₀₋₄N(R°)₂, —(CH₂)₀₋₄C(O)OR°,and —(CH₂)₀₋₄C(O)NR°₂.

Embodiment 24. The compound according to embodiment 23, wherein R° isselected from hydrogen, C₁₋₆ aliphatic, —CH₂Ph, —O(CH₂)₀₋₁Ph, —CH₂—(5-to 6-membered heteroaryl ring), a 5- to 6-membered saturated, partiallyunsaturated, or aryl ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur, and an 8- to 10-membered bicyclicaryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, and sulfur, or: two independent occurrences of R°, takentogether with their intervening atom(s), form a 3- to 12-memberedsaturated, partially unsaturated, or aryl mono- or bicyclic ring having0-4 heteroatoms independently selected from nitrogen, oxygen, andsulfur.

Embodiment 25. The compound according to embodiment 20, wherein R^(x) isC₁₋₄ aliphatic optionally substituted with a group selected fromhalogen, —R°, —OR°, —N(R°)₂, —C(O)OR°, and —C(O)NR°₂.

Embodiment 26. The compound according to embodiment 20, wherein R^(x) isC₁₋₄ aliphatic optionally substituted with halogen.

Embodiment 27. The compound according to embodiment 26, wherein R^(x) isselected from —CH₃, —CF₃, —CHF₂, and CH₂F.

Embodiment 28. The compound according to embodiment 25, wherein R^(x) isselected from —CH₂R°, —CH₂OR°, —CH₂N(R°)₂, —CH₂C(O)OR°, and—CH₂C(O)N(R°)₂.

Embodiment 29. The compound according to embodiment 28, wherein R^(x) isselected from —CH₂OH, —CH₂OCH₃, —CH₂C(O)NH₂, —CH₂C(O)NHCH₃, and—CH₂C(O)N(CH₃)₂.

Embodiment 30. The compound according to any one of embodiments 1-29,wherein R¹ is an optionally substituted 5- to 6-membered heteroaryl ringhaving 1-3 heteroatoms independently selected from oxygen, nitrogen, andsulfur.

Embodiment 31. The compound according to embodiment 30, wherein R¹ is anoptionally substituted 5-membered heteroaryl ring having 1-3 heteroatomsindependently selected from oxygen, nitrogen, and sulfur.

Embodiment 32. The compound according to embodiment 31, wherein R¹ is anoptionally substituted 5-membered heteroaryl ring having 1-2 heteroatomsindependently selected from oxygen, nitrogen, and sulfur.

Embodiment 33. The compound according to embodiment 30, wherein R¹ is anoptionally substituted 6-membered heteroaryl ring having 1-3 nitrogenatoms.

Embodiment 34. The compound according to embodiment 33, wherein R¹ is anoptionally substituted 6-membered heteroaryl ring having 1-2 nitrogenatoms.

Embodiment 35. The compound according to embodiment 30, wherein R¹ isselected from

Embodiment 36. The compound according to embodiment 35, wherein R¹ isselected from

Embodiment 37. The compound according to any one of embodiments 1-36,wherein L is an optionally substituted C₁₋₂ aliphatic chain wherein oneor two carbon atoms in the aliphatic chain are optionally replaced by agroup independently selected from —O—, —N(R)—, —S—, —C(O)—, —C(O)N(R)—,—N(R)C(O)—, —C(O)O—, —OC(O)—, —S(O)₂N(R)—, —N(R)S(O)₂—, and a bivalent3-to 5-membered monocyclic, bicyclic, or bridged bicyclic carbocyclicring.

Embodiment 38. The compound according to embodiment 37, wherein L is anoptionally substituted C₁₋₂ aliphatic chain wherein one carbon atom inthe aliphatic chain is replaced by a group selected from ——C(O)N(R)—,—N(R)C(O)—, —C(O)O—, —OC(O)—, —S(O)₂N(R)—, and —N(R)S(O)₂—.

Embodiment 39. The compound according to embodiment 37 or 38, wherein Lis an optionally substituted C₁₋₂ aliphatic chain wherein one carbonatom in the aliphatic chain is replaced by a group selected from—C(O)N(H)—, —N(H)C(O)—, —C(O)O—, —OC(O)—, —S(O)₂N(H)—, and —N(H)S(O)₂—.

Embodiment 40. The compound according to embodiment 37 or 38, wherein Lis an optionally substituted C₁₋₂ aliphatic chain wherein one carbonatom in the aliphatic chain is replaced by a group selected from—C(O)N(R)— and —N(R)C(O)—.

Embodiment 41. The compound according to embodiment 40, wherein L is anoptionally substituted C₁₋₂ aliphatic chain wherein one carbon atom inthe aliphatic chain is replaced by a group selected from —C(O)N(H)— and—N(H)C(O)—.

Embodiment 42. The compound according to any one of embodiments 1-36,wherein L is an optionally substituted C₃₋₄ aliphatic chain wherein oneor two carbon atoms in the aliphatic chain are optionally replaced by agroup independently selected from —O—, —N(R)—, —S—, —C(O)—, —C(O)N(R)—,—N(R)C(O)—, —C(O)O—, —OC(O)—, —S(O)₂N(R)—, —N(R)S(O)₂—, and a bivalent3-to 5-membered monocyclic, bicyclic, or bridged bicyclic carbocyclicring.

Embodiment 43. The compound according to embodiment 42, wherein L is anoptionally substituted C₃₋₄ aliphatic chain wherein one or two carbonatoms in the aliphatic chain are optionally replaced by a groupindependently selected from —O—, —N(R)—, —S—, and —C(O)—.

Embodiment 44. The compound according to embodiment 42 or 43, wherein Lis an optionally substituted C₃₋₄ aliphatic chain wherein one or twocarbon atoms in the aliphatic chain are optionally replaced by a groupindependently selected from —O—, —N(H)—, —S—, and —C(O)—

Embodiment 45. The compound according to any one of embodiments 1-36,wherein L is an optionally substituted C₃₋₄ aliphatic chain wherein onecarbon atom in the aliphatic chain is replaced by a group selected from—C(O)N(R)— and —N(R)C(O)—.

Embodiment 46. The compound according to embodiment 45, wherein L is anoptionally substituted C₃₋₄ aliphatic chain wherein one carbon atom inthe aliphatic chain is replaced by a group selected from —C(O)N(H)— and—N(H)C(O)—.

Embodiment 47. The compound according to any one of embodiments 1-36,wherein L is an optionally substituted C₁₋₄ aliphatic chain wherein twocarbon atoms in the aliphatic chain are replaced by —N(R)— and —C(O)—.

Embodiment 48. The compound according to any one of embodiments 1-36,wherein L is an optionally substituted C₁₋₄ aliphatic chain wherein atleast one carbon atom in the aliphatic chain is replaced by —C(O)N(R)—.

Embodiment 49. The compound according to embodiment 48, wherein L isselected from

Embodiment 50. The compound according to embodiment 49, wherein L isselected from

Embodiment 51. The compound according to any one of embodiments 1-38,40, 42, 43, 45, 47, 48, and 49, wherein R is hydrogen.

Embodiment 52. The compound according to any one of embodiments 1-38,40, 42, 43, 45, 47, 48, and 49, wherein R is —CH₃.

Embodiment 53. The compound according to any one of embodiments 1-38,40, 42, 43, 45, 47, 48, and 49, wherein R is optionally substituted C₁₋₆aliphatic.

Embodiment 54. The compound according to embodiment 53, wherein R isaliphatic optionally substituted with oxo and OR°.

Embodiment 55. The compound according to embodiment 54, wherein R° isC₁₋₆ aliphatic.

Embodiment 56. The compound according to embodiment 53, wherein R ismethyl or ethyl.

Embodiment 57. The compound according to any one of embodiments 1-56,wherein R² is hydrogen.

Embodiment 58. The compound according to any one of embodiments 1-56,wherein R² is halogen, N(R′)₂, OR′, or an optionally substituted groupselected from C₁₋₆ aliphatic, a 3- to 7-membered saturated or partiallyunsaturated heterocyclic ring having 1-3 heteroatoms independentlyselected from oxygen, nitrogen, and sulfur, phenyl, a 5- to 6-memberedheteroaryl ring having 1-3 heteroatoms independently selected fromoxygen, nitrogen, and sulfur, a 8- to 10-membered bicyclic saturated,partially unsaturated or aryl carbocyclic ring, a 8- to 10-memberedbicyclic saturated or partially unsaturated heterocyclic ring having 1-3heteroatoms independently selected from oxygen, nitrogen, and sulfur,and a 8- to 10-membered bicyclic heteroaryl ring having 1-3 heteroatomsindependently selected from oxygen, nitrogen, and sulfur.

Embodiment 59. The compound according to embodiment 58, wherein R² isoptionally substituted C₁₋₆ aliphatic.

Embodiment 60. The compound according to embodiment 59, wherein R² ismethyl or ethyl.

Embodiment 61. The compound according to embodiment 59, wherein R² isoptionally substituted cyclohexyl.

Embodiment 62. The compound according to embodiment 58, wherein R² isoptionally substituted phenyl.

Embodiment 63. The compound according to embodiment 58, wherein R² is anoptionally substituted 5- to 6-membered heteroaryl ring having 1-3heteroatoms independently selected from oxygen, nitrogen, and sulfur.

Embodiment 64. The compound according to embodiment 63, wherein R² is anoptionally substituted 5-membered heteroaryl ring having 1-2 heteroatomsindependently selected from oxygen, nitrogen, and sulfur.

Embodiment 65. The compound according to embodiment 63 or 64, wherein R²is an optionally substituted group selected from thiophenyl, pyrazolyl,and imidazolyl.

Embodiment 66. The compound according to embodiment 63, wherein R² is anoptionally substituted 6-membered heteroaryl ring having 1-3 nitrogenatoms.

Embodiment 67. The compound according to embodiment 66, wherein R² is anoptionally substituted 6-membered heteroaryl ring having 1-2 nitrogenatoms.

Embodiment 68. The compound according to embodiment 67, wherein R² is anoptionally substituted group selected from pyridinyl or pyrimidinyl.

Embodiment 69. The compound according to embodiment 58, wherein R² isselected from the group consisting of

Embodiment 70. The compound according to any one of embodiments 1-69,wherein R³ is hydrogen.

Embodiment 71. The compound according to any one of embodiment 70,wherein R³ is methyl, ethyl, or isopropyl.

Embodiment 72. The compound according to any one of embodiments 1-71,wherein R^(y) is hydrogen.

Embodiment 73. The compound according to any one of embodiments 1-71,wherein R^(y) is halogen.

Embodiment 74. The compound according to any one of embodiments 1-71,wherein R^(y) is cyano.

Embodiment 75. The compound according to any one of embodiments 1-71,wherein R^(y) is OR″.

Embodiment 76. The compound according to any one of embodiments 1-71,wherein R^(y) is SR″.

Embodiment 77. The compound according to any one of embodiments 1-71,wherein R^(y) is N(R″)₂.

Embodiment 78. The compound according to any one of embodiments 75-77,wherein R″ is selected from hydrogen and optionally substituted C₁₋₆aliphatic.

Embodiment 79. The compound according to embodiment 78, wherein R″ isselected from hydrogen and optionally substituted C₁₋₄ aliphatic.

Embodiment 80. The compound according to any one of embodiments 75, 78,and 79, wherein R^(y) is OH, OCH₃, and OCH₂CH₃.

Embodiment 81. The compound according to any one of embodiments 76, 78,and 79, wherein R^(y) is SH, SCH₃, and SCH₂CH₃.

Embodiment 82. The compound according to any one of embodiments 77-79,wherein R^(y) is selected from NH₂, NHCH₃, NHCH₂CH₃, N(CH₃)₂, andN(CH₂CH₃)₂.

Embodiment 83. The compound according to any one of embodiments 1-71,wherein R^(y) is optionally substituted C₁₋₄ aliphatic.

Embodiment 84. The compound according to embodiment 83, wherein R^(y) isoptionally substituted C₃₋₄ aliphatic.

Embodiment 85. The compound according to embodiment 84, wherein R^(y) isselected from tert-butyl,

Embodiment 86. The compound according to embodiment 83, wherein R^(y) isC₁₋₄ aliphatic optionally substituted with a group selected fromhalogen, —(CH₂)₀₋₄R°, —(CH₂)₀₋ ₄OR°, —(CH₂)₀₋₄N(R°)₂, —(CH₂)₀₋₄C(O)OR°,and —(CH₂)₀₋₄C(O)NR°₂.

Embodiment 87. The compound according to embodiment 86, wherein R° isselected from hydrogen, C₁₋₆ aliphatic, —CH₂Ph, —O(CH₂)₀₋₁Ph, —CH₂—(5-to 6-membered heteroaryl ring), a 5- to 6-membered saturated, partiallyunsaturated, or aryl ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur, and an 8- to 10-membered bicyclicaryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, and sulfur, or: two independent occurrences of R°, takentogether with their intervening atom(s), form a 3- to 12-memberedsaturated, partially unsaturated, or aryl mono- or bicyclic ring having0-4 heteroatoms independently selected from nitrogen, oxygen, andsulfur.

Embodiment 88. The compound according to embodiment 83, wherein R^(y) isC₁₋₄ aliphatic optionally substituted with a group selected fromhalogen, —R°, —OR°, —N(R°)₂, —C(O)OR°, and —C(O)NR°₂.

Embodiment 89. The compound according to embodiment 83, wherein R^(y) isC₁₋₄ aliphatic optionally substituted with halogen.

Embodiment 90. The compound according to embodiment 89, wherein R^(y) isselected from —CH₃, —CF₃, —CHF₂, and CH₂F.

Embodiment 91. The compound according to embodiment 88, wherein R^(y) isselected from —CH₂R°, —CH₂OR°, —CH₂N(R°)₂, —CH₂C(O)OR°, and—CH₂C(O)N(R°)₂.

Embodiment 92. The compound according to embodiment 91, wherein R^(y) isselected from —CH₂OH, —CH₂OCH₃, —CH₂C(O)NH₂, —CH₂C(O)NHCH₃, and—CH₂C(O)N(CH₃)₂.

Embodiment 93. The compound according to embodiment 1, wherein thecompound is a compound of Formulae I-a, I-b, I-c, I-d, I-e, I-f, andI-g:

or a pharmaceutically acceptable salt thereof.

Embodiment 94. The compound according to embodiment 1, embodiment 7, orembodiment 93, wherein the compound is a compound of Formulae I-a-i,I-b-i, I-c-i, I-d-i, I-e-i, I-f-i, and I-g-i:

or a pharmaceutically acceptable salt thereof.

Embodiment 95. The compound according to embodiment 1, embodiment 8, orembodiment 93, wherein the compound is a compound of Formulae I-a-ii,I-b-ii, I-c-ii, I-d-ii, I-e-ii, I-f-ii, and I-g-ii:

or a pharmaceutically acceptable salt thereof.

Embodiment 96. The compound according to embodiment 1, embodiment 9, orembodiment 93, wherein the compound is a compound of Formulae I-a-iii,I-b-iii, I-c-iii, I-d-iii, I-e-iii, I-f-iii, and I-g-iii:

or a pharmaceutically acceptable salt thereof.

Embodiment 97. The compound according to embodiment 1, wherein thecompound is a compound of Formulae I-a-iv, I-a-v, I-a-vi, I-a-vii,I-b-iv, I-b-v, I-b-vi, I-b-vii, I-c-iv, I-c-v, I-c-vi, I-c-vii, I-d-iv,I-d-v, I-d-vi, I-d-vii, I-e-iv, I-e-v, I-e-vi, I-e-vii, I-f-iv, 1-f-v,I-f-vi, I-f-vii, I-g-iv, I-g-v, I-g-vi, and I-g-vii:

or a pharmaceutically acceptable salt thereof.

Embodiment 98. The compound according to embodiment 1, wherein thecompound is a compound of Formulae I-a-viii, I-a-ix, I-a-x, I-a-xi,I-b-viii, I-b-ix, I-b-x, I-b-xi, I-c-viii, I-c-ix, I-c-x, I-c-xi,I-d-viii, I-d-ix, I-d-x, I-d-xi, I-e-viii, I-e-ix, I-e-x, I-e-xi,I-f-viii, I-f-ix, I-f-x, I-f-xi, I-g-viii, I-g-ix, I-g-x, and I-g-xi:

or a pharmaceutically acceptable salt thereof.

Embodiment 99. The compound according to embodiment 1, wherein thecompound is a compound of Formulae I-a-xii, I-a-xiii, I-a-xiv, I-a-xv,I-b-xii, I-b-xiii, I-b-xiv, I-b-xv, I-c-xii, I-c-xiii, I-c-xiv, I-c-xv,I-d-xii, I-d-xiii, I-d-xiv, I-d-xv, I-e-xii, I-e-xiii, I-e-xiv, I-e-xv,I-f-xii, I-f-xiii, I-f-xiv, I-f-xv, I-g-xii, I-g-xiii, I-g-xiv, andI-g-xv:

or a pharmaceutically acceptable salt thereof.

Embodiment 100. A pharmaceutical composition comprising a compoundaccording to any one of embodiments 1-99 and a pharmaceuticallyacceptable carrier.

Embodiment 101. A method comprising a step of:

administering a compound according to any one of embodiments 1-99 to asubject who (i) has a condition characterized by axonal degeneration or(ii) is at risk of developing a condition characterized by axonaldegeneration.

Embodiment 102. A method of treating or preventing axonal degenerationcomprising administering to a subject in need thereof a compoundaccording to any one of embodiments 1-99.

Embodiment 103. A method of inhibiting SARM1 comprising contacting abiological sample with a compound according to any one of embodiments1-99.

Embodiment 104. A compound of Formula II:

or a pharmaceutically acceptable salt thereof, wherein:

-   R¹ is a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms    independently selected from oxygen, nitrogen, and sulfur, wherein    the 5- to 6-membered heteroaryl ring is optionally substituted with    fluorine or methyl;-   R² is a 5- to 6-membered heteroaryl ring having 1 heteroatom    selected from nitrogen and sulfur, or phenyl, wherein the 5- to    6-membered heteroaryl ring or phenyl is optionally substituted with    1-2 groups selected from fluorine and chlorine;-   R⁴ is hydrogen or methyl;-   Q is N or CH;-   X, Y and Z are independently CR⁵ or a nitrogen atom, provided that    no more than two X, Y and Z are nitrogen atoms; and-   R⁵ is hydrogen or methyl.

In a further embodiment, the compound is selected from:

or a pharmaceutically acceptable salt thereof.

Compositions

In some embodiments, a compound of Formula I/II may be provided in acomposition, e.g., in combination (e.g., admixture) with one or moreother components.

In some embodiments, the present disclosure provides compositions thatcomprise and/or deliver a compound of Formula I/II, or an activemetabolite thereof, e.g., when contacted with or otherwise administeredto a system or environment e.g., which system or environment may includeSARM1 NADase activity; in some embodiments, administration of such acomposition to the system or environment achieves inhibition of SARM1activity as described herein.

In some embodiments, a provided composition as described herein may be apharmaceutical composition in that it comprises an active agent and oneor more pharmaceutically acceptable excipients; in some suchembodiments, a provided pharmaceutical composition comprises and/ordelivers a compound of Formula I/II, or an active metabolite thereof toa relevant system or environment (e.g., to a subject in need thereof) asdescribed herein.

In some embodiments, one or more compounds of Formula I/II is providedand/or utilized in a pharmaceutically acceptable salt form.

Among other things, the present disclosure provides compositionscomprising a compound of Formula I/II, or a pharmaceutically acceptablesalt or derivative thereof, and a pharmaceutically acceptable carrier,adjuvant, or vehicle. The amount of compound in provided compositions issuch that is effective to measurably inhibit axonal degeneration in abiological sample or in a patient. In certain embodiments, a providedcompound or composition is formulated for administration to a patient inneed of such composition. The compounds and compositions, according tothe methods of the present disclosure, may be administered using anyamount and any route of administration effective for treating orlessening the severity of any disease or disorder described herein.Provided compounds are preferably formulated in dosage unit form forease of administration and uniformity of dosage. The expression “dosageunit form” as used herein refers to a physically discrete unit of agentappropriate for the patient to be treated. It will be understood,however, that the total daily usage of the provided compounds andcompositions will be decided by the attending physician within the scopeof sound medical judgment. The specific effective dose level for anyparticular patient or organism will vary from subject to subject,depending on a variety of factors, including the disorder being treatedand the severity of the disorder; the activity of the specific compoundemployed; the specific composition employed and its route ofadministration; the species, age, body weight, sex and diet of thepatient; the general condition of the subject; the time ofadministration; the rate of excretion of the specific compound employed;the duration of the treatment; drugs used in combination or coincidentalwith the specific compound employed, and the like.

Provided compositions may be administered orally, parenterally, byinhalation or nasal spray, topically (e.g., as by powders, ointments, ordrops), rectally, buccally, intravaginally, intraperitoneally,intracisternally or via an implanted reservoir, depending on theseverity of the condition being treated. Preferably, the compositionsare administered orally, intraperitoneally or intravenously. In certainembodiments, provided compounds are administered orally or parenterallyat dosage levels of about 0.01 mg/kg to about 50 mg/kg, of subject bodyweight per day, one or more times a day, to obtain the desiredtherapeutic effect.

The term “parenteral” as used herein includes subcutaneous, intravenous,intramuscular, intra-articular, intra-synovial, intrasternal,intrathecal, intrahepatic, intralesional and intracranial injection orinfusion techniques. Sterile injectable forms of provided compositionsmay be aqueous or oleaginous suspension. These suspensions may beformulated according to techniques known in the art using suitabledispersing or wetting agents and suspending agents. The sterileinjectable preparation may also be a sterile injectable solution orsuspension in a nontoxic parenterally acceptable diluent or solvent, forexample, as a solution in 1,3-butanediol. Among the acceptable vehiclesand solvents that may be employed are water, Ringer’s solution andisotonic sodium chloride solution. In addition, sterile, fixed oils areconventionally employed as a solvent or suspending medium.

For this purpose, any bland fixed oil may be employed includingsynthetic mono-or di-glycerides. Fatty acids, such as oleic acid and itsglyceride derivatives are useful in the preparation of injectables, asare natural pharmaceutically-acceptable oils, such as olive oil orcastor oil, especially in their polyoxyethylated versions. These oilsolutions or suspensions may also contain a long-chain alcohol diluentor dispersant, such as carboxymethyl cellulose or similar dispersingagents that are commonly used in the formulation of pharmaceuticallyacceptable dosage forms including emulsions and suspensions. Othercommonly used surfactants, such as Tweens, Spans and other emulsifyingagents or bioavailability enhancers which are commonly used in themanufacture of pharmaceutically acceptable solid, liquid, or otherdosage forms may also be used for the purposes of formulation.

Injectable formulations can be sterilized, for example, by filtrationthrough a bacterial-retaining filter, or by incorporating sterilizingagents in the form of sterile solid compositions which can be dissolvedor dispersed in sterile water or other sterile injectable medium priorto use.

In order to prolong the effect of a provided compound, it is oftendesirable to slow the absorption of the compound from subcutaneous orintramuscular injection. This may be accomplished by the use of a liquidsuspension of crystalline or amorphous material with poor watersolubility. The rate of absorption of the compound then depends upon itsrate of dissolution that, in turn, may depend upon crystal size andcrystalline form. Alternatively, delayed absorption of a parenterallyadministered compound form is accomplished by dissolving or suspendingthe compound in an oil vehicle. Injectable depot forms are made byforming microencapsule matrices of the compound in biodegradablepolymers such as polylactide-polyglycolide. Depending upon the ratio ofcompound to polymer and the nature of the particular polymer employed,the rate of compound release can be controlled. Examples of otherbiodegradable polymers include poly(orthoesters) and poly(anhydrides).Depot injectable formulations are also prepared by entrapping thecompound in liposomes or microemulsions that are compatible with bodytissues.

Pharmaceutically acceptable compositions described herein may be orallyadministered in any orally acceptable dosage form including, but notlimited to, capsules, tablets, aqueous suspensions or solutions. In suchsolid dosage forms the active compound may be admixed with at least oneinert diluent such as sucrose, lactose or starch. Such dosage forms mayalso comprise, as is normal practice, additional substances other thaninert diluents, e.g., lubricants and other tableting aids such amagnesium stearate and microcrystalline cellulose. When aqueoussuspensions are required for oral use, the active ingredient is combinedwith emulsifying and suspending agents. If desired, certain sweetening,flavoring or coloring agents may also be added.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar--agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and/or i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents. The active compounds canalso be in micro-encapsulated form with one or more excipients as notedabove.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like. The solid dosage forms of tablets, dragees, capsules, pills,and granules can be prepared with coatings and shells such as entericcoatings (i.e. buffering agents) and other coatings well known in thepharmaceutical formulating art. They may optionally contain opacifyingagents and can also be of a composition that they release the activeingredient(s) only, or preferentially, in a certain part of theintestinal tract, optionally, in a delayed manner. Examples of embeddingcompositions that can be used include polymeric substances and waxes.

Liquid dosage forms for oral administration include, but are not limitedto, pharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active compounds,the liquid dosage forms may contain inert diluents commonly used in theart such as, for example, water or other solvents, solubilizing agentsand emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor, and sesame oils),glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fattyacid esters of sorbitan, and mixtures thereof. Besides inert diluents,the oral compositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Alternatively, pharmaceutically acceptable compositions described hereinmay be administered in the form of suppositories for rectal or vaginaladministration. These can be prepared by mixing the compounds of thepresent disclosure with suitable non-irritating excipients or carriersthat are solid at room temperature but liquid at body (e.g. rectal orvaginal) temperature and therefore will melt in the rectum or vaginalcavity to release the active compound. Such materials include cocoabutter, a suppository wax (e.g., beeswax) and polyethylene glycols.

Pharmaceutically acceptable compositions described herein may also beadministered topically, especially when the target of treatment includesareas or organs readily accessible by topical application, includingdiseases of the eye, the skin, or the lower intestinal tract. Topicalapplication for the lower intestinal tract can be effected in a rectalsuppository formulation (see above) or in a suitable enema formulation.

Dosage forms for topical or transdermal administration of a providedcompound include ointments, pastes, creams, lotions, gels, powders,solutions, sprays, inhalants or patches. The active component is admixedunder sterile conditions with a pharmaceutically acceptable carrier andany needed preservatives or buffers as may be required. Ophthalmicformulations, ear drops, and eye drops are also contemplated as beingwithin the scope of this disclosure. Additionally, the presentdisclosure contemplates the use of transdermal patches, which have theadded advantage of providing controlled delivery of a compound to thebody. Such dosage forms can be made by dissolving or dispensing thecompound in the proper medium. Absorption enhancers can also be used toincrease the flux of the compound across the skin. The rate can becontrolled by either providing a rate controlling membrane or bydispersing the compound in a polymer matrix or gel.

For topical applications, provided pharmaceutically acceptablecompositions may be formulated in a suitable ointment containing theactive component suspended or dissolved in one or more carriers.Carriers for topical administration of compounds of this disclosureinclude, but are not limited to, mineral oil, liquid petrolatum, whitepetrolatum, propylene glycol, polyoxyethylene, polyoxypropylenecompound, emulsifying wax and water. Alternatively, providedpharmaceutically acceptable compositions can be formulated in a suitablelotion or cream containing the active components suspended or dissolvedin one or more pharmaceutically acceptable carriers. Suitable carriersinclude, but are not limited to, mineral oil, sorbitan monostearate,polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol,benzyl alcohol and water.

For ophthalmic use, provided pharmaceutically acceptable compositionsmay be formulated as micronized suspensions in isotonic, pH adjustedsterile saline, or, preferably, as solutions in isotonic, pH adjustedsterile saline, either with or without a preservative such asbenzylalkonium chloride. Alternatively, for ophthalmic uses, thepharmaceutically acceptable compositions may be formulated in anointment such as petrolatum.

Pharmaceutically acceptable compositions of this disclosure may also beadministered by nasal aerosol or inhalation. Such compositions areprepared according to techniques well-known in the art of pharmaceuticalformulation and may be prepared as solutions in saline, employing benzylalcohol or other suitable preservatives, absorption promoters to enhancebioavailability, fluorocarbons, and/or other conventional solubilizingor dispersing agents.

Most preferably, pharmaceutically acceptable compositions of thisdisclosure are formulated for oral administration.

Identification and/or Characterization of Compounds and/or Compositions

Among other things, the present disclosure provides various technologiesfor identification and/or characterization of compounds and/orcompositions as described herein. For example, the present disclosureprovides various assays for assessing SARM1 inhibitory activity, andspecifically for assessing SARM1 inhibitory activity.

In some embodiments, performance of one or more compounds orcompositions of interest in an assay as described herein is comparedwith that of an appropriate reference. For example, in some embodiments,a reference may be absence of the relevant compound or composition.Alternatively or additionally, in some embodiments, a reference may bepresence of an alternative compound or composition, e.g., whichalternative compound or composition has known performance (e.g., as apositive control or a negative control, as is understood in the art) inthe relevant assay. In some embodiments, a reference may be analternative but comparable set of conditions (e.g., temperature, pH,salt concentration, etc.). In some embodiments, a reference may beperformance of the compound or composition with respect to a SARM1variant.

Still further alternatively or additionally, in some embodiments,performance of one or more compounds or compositions of interest in anassay as described herein may be assessed in the presence of anappropriate reference compound or composition, for example, so thatability of the compound or composition to compete with the reference isdetermined.

In some embodiments, a plurality of compounds or compositions ofinterest may be subjected to analysis in a particular assay and/orcompared with the same reference. In some embodiments, such a pluralityof compounds or compositions may be or include a set of compounds orcompositions that is considered to be a “library” because multiplemembers share one or more features (e.g., structural elements, sourceidentity, synthetic similarities, etc.).

Certain exemplary assays that may be useful in the practice of thepresent disclosure are exemplified in the Examples below. Those skilledin the art, reading the present disclosure, will be aware that useful orrelevant systems for identifying and/or characterizing compounds and/orcompositions in accordance with the present disclosure are not limitedto those included in the Examples, or otherwise discussed below.

In some embodiments, compounds and/or compositions may be identifiedbased on and/or characterized by one or more activities orcharacteristics such as, for example: promoting axonal integrity,cytoskeletal stability, and/or neuronal survival. In some embodiments,provided SARM1 inhibitors inhibit catabolism of NAD+ to by SARM1. Insome embodiments, provided SARM1 inhibitors slow the rate of NAD+catabolism.

In some embodiments, provided SARM1 inhibitors reduce or inhibit bindingof NAD+ by SARM1. In some embodiments, provided SARM1 inhibitors bind toSARM1 within a pocket comprising one or more catalytic residues (e.g., acatalytic cleft of SARM1). Examples of such catalytic residues includethe glutamic acid at position 642 (E642).

In some embodiments, provided SARM1 inhibitors disrupt and/or preventmultimerization of the TIR1 domain of SARM1. In some embodiments,provided SARM1 inhibitors disrupt the multimerization of the SAMdomains. In some embodiments, provided SARM1 inhibitors disrupt theaxonal signaling cascade that leads to depletion of NAD+.

In some embodiments, the present disclosure provides assays useful foridentifying and/or characterizing one or more activities and/orcharacteristics of compound and/or compositions of interest. Forexample, in some embodiments, the present disclosure provides in vitro,cellular, and/or in vivo systems for assessing one or more suchactivities and/or characteristics.

SARM1 Activity Assays

In some embodiments, a method of identifying a SARM1 inhibitorcomprises: a) providing a mixture comprising i) a mutant or fragment ofSARM1, ii) NAD+ and iii) a candidate inhibitor, wherein the mutant orfragment has constitutive activity; b) incubating the mixture; c)quantifying NAD+ in the mixture after the incubating; and d) identifyingthe candidate inhibitor compound as an inhibitor if the amount of NAD+is greater than that of a control mixture that does not contain thecandidate inhibitor.

In some embodiments, provided are methods of identifying a SARM1inhibitor, comprising: a) providing a mixture comprising i) afull-length SARM1, ii) NAD+ and iii) a candidate inhibitor, wherein thefull-length SARM1 has constitutive activity; b) incubating the mixture;c) quantifying NAD+ and ADPR (or cADPR) in the mixture after theincubating; d) determining the molar ratio of NAD+: ADPR (or cADPR); ande) identifying the candidate inhibitor compound as an inhibitor if themolar ratio is greater than that of a control mixture that does notcontain the candidate inhibitor.

In some embodiments, provided are methods of identifying a SARM1inhibitor, comprising: a) providing a mixture comprising a solid supportto which is bound i) a full-length SARM1 and at least one tag, ii) NAD+,and iii) a candidate inhibitor; b) incubating the mixture; c)quantifying the NAD+ after the incubating; and d) identifying thecandidate inhibitor compound as a SARM1 inhibitor if the concentrationof NAD+ is greater than that of a control.

SARM1 Binding Assays

In some embodiments, the efficacy of provided SARM1 inhibitors can bedetermined according to, e.g., the assays described in WO 2018/057989,published on Mar. 29, 2018, which is hereby incorporated by reference inits entirety. In some embodiments, the provided SARM1 inhibitors can beapplied to a solution containing SARM1 or a fragment thereof. In someembodiments, the provided SARM1 inhibitors can be applied to an in vitrosystem. In some embodiments, the provided SARM1 inhibitors can beapplied to an in vivo. In some embodiments, the provided SARM1inhibitors can be applied to a patient. In some embodiments, a SARM1inhibitor can be mixed with SARM1 or fragment thereof that has beenlabeled with an epitope tag. In some embodiments, the amount of boundSARM1 inhibitor can be compared to the amount of unbound SARM1inhibitor, yielding the affinity for the SARM1 inhibitor.

In some embodiments, the mutant or fragment of SARM1 is a SAM-TIRfragment having constitutive activity. Fragments of SARM1 havingconstitutive activity include, for example and without limitation, aSARM1 with the autoinhibitory domain deleted; at least one pointmutation of SARM1 that renders the autoinhibitory domain inactive; afragment of SARM1 containing a TIR domain; or a fragment of SARM1consisting of SAM and TIR domains. In some embodiments a SARM1polypeptide can include one or more additional amino acid sequences thatcan act as tags, such as a His tag, a streptavidin tag, or a combinationthereof. In some embodiments a SARM1 polypeptide can include a tag atthe amino terminus, at the carboxy terminus, or a combination thereof.In some embodiments, SARM1 or fragment thereof labeled with an epitopetag can be used to measure the binding efficacy of provided SARM1inhibitors.

Purification of SARAIII-TIR Domains

In some embodiments, a SARM1-TIR domain can be engineered with variousprotein, or epitope, tags that can be useful, for example, inpurification. In some embodiments, the present disclosure also providesfor a NRK1-HEK293T cell line comprising HEK293T cells transformed with aNicotinamide Riboside Kinase 1 (NRK1). In some embodiments, HEK293Tcells transformed or transfected with a DNA sequence encodingNicotinamide Riboside Kinase 1 (NRK1). In some embodiments, the DNAencoding NRK1 can be genomic or cDNA. In some embodiments, HEK293T cellsare stably or transiently transfected with DNA encoding NRK1 from asource exogenous to the host cell. In some embodiments, HEK293T cellsare stably or transiently transfected with DNA encoding NRK1 such thatthe cells express NRK1 at an elevated level compared to control cells.In some embodiments, DNA encoding NRK1 is under the control of one ormore exogenous regulatory DNA sequences such as a promoter, an enhanceror a combination thereof. In some embodiments, a combination of a DNAsequences encoding NRK1 and regulatory sequences is a non-naturallyoccurring combination. In some embodiments, DNA encoding NRK1, eithergenomic or cDNA, comprises an expression vector such as an FCIVexpression vector. In some embodiments, DNA encoding NRK1 is derivedfrom genomic DNA or cDNA from a vertebrate or invertebrate species suchas, but not limited to, human, mouse, zebrafish or a Drosophila. In someconfigurations, the NRK1 DNA is a human NRK1 DNA.

Applications and Uses

The present disclosure provides a variety of uses and applications forcompounds and/or compositions as described herein, for example in lightof their activities and/or characteristics as described herein. In someembodiments, such uses may include therapeutic and/or diagnostic uses.Alternatively, in some embodiments such uses may include research,production, and/or other technological uses.

In one aspect, the present disclosure provides methods comprisingadministering one or more compounds of Formula I/II to a subject, e.g.,to treat, prevent, or reduce the risk of developing one or moreconditions characterized by axonal degeneration. In some suchembodiments, the compound of Formula I/II is a SARM1 inhibitor.

Another embodiment of the present disclosure relates to a method ofinhibiting SARM1 activity in a patient comprising steps of administeringto said patient a provided compound, or a composition comprising saidcompound.

Inhibition of enzymes in a biological sample is useful for a variety ofpurposes that are known to one of skill in the art. Examples of suchpurposes include, but are not limited to biological assays, geneexpression studies, and biological target identification.

In certain embodiments, the present disclosure relates to a method oftreating axonal degeneration in a biological sample comprising the stepof contacting said biological sample with a compound or composition ofFormula I/II. In some embodiments, one or more compounds and/orcompositions as described herein are useful, for example as a method offor inhibiting the degradation of neurons derived from a subject. Insome embodiments, one or more compounds and/or compositions as describedherein, are useful for inhibiting the degeneration of a neuron, orportion thereof, cultured in vitro. In some embodiments, one or morecompounds and/or compositions as described herein, are useful asstabilizing agents to promote in vitro neuronal survival.

In some embodiments, provided compounds and/or compositions inhibitNADase activity of SARM1. Alternatively or additionally, in someembodiments, provided compounds alleviate one or more attributes ofneurodegeneration. In some embodiments, the present disclosure providesmethods of treating a neurodegenerative disease or disorder associatedwith axonal degeneration.

In some embodiments, one or more compounds and/or compositions asdescribed herein are useful, for example, in the practice of medicine.In some embodiments, one or more compounds and/or compositions asdescribed herein are useful, for example, to treat, prevent, orameliorate axonal degeneration (e.g., one or more features orcharacteristics thereof). In some embodiments, one or more compoundsand/or compositions as described herein are useful, for example toinhibit axonal degeneration, including axonal degeneration that resultsfrom reduction or depletion of NAD+. In some embodiments, one or morecompounds and/or compositions as described herein are useful, forexample to prevent the axon distal to an axonal injury fromdegenerating.

In some embodiments, one or more compounds and/or compositions asdescribed herein are useful, for example as a method for inhibiting thedegradation of a peripheral nervous system neuron or a portion thereof.In some embodiments, one or more compounds and/or compositions asdescribed herein are useful, for example as a method for inhibiting orpreventing degeneration of a central nervous system (neuron) or aportion thereof. In some embodiments, one or more compounds orcompositions as described herein is characterized that, whenadministered to a population of subjects, reduces one or more symptomsor features of neurodegeneration. For example, in some embodiments, arelevant symptom or feature may be selected from the group consisting ofextent, rate, and/or timing of neuronal disruption.

In certain embodiments, the present disclosure provides compounds thatare useful, for example, as analytical tools, as probes in biologicalassays, or as therapeutic agents in accordance with the presentdisclosure. Compounds provided by this disclosure are also useful forthe study of SARM1 activity in biological and pathological phenomena andthe comparative evaluation of new SARM1 activity inhibitors in vitro orin vivo. In certain embodiments, the present disclosure provides assaysfor identifying and/or characterizing compounds and/or compositionsprovided herein. In some embodiments, provided assays utilize particularreagents and/or systems (e.g., certain vector constructs and/orpolypeptides) useful in assaying SARM1 activity. For example, in someembodiments, provided assays may utilize, for example, a SAM-TIR inwhich the SARM1 N-terminal auto-inhibitory domain is deleted, and/or oneor more tagged versions of a TIR domain.

In some embodiments, one or more compounds and/or compositions asdescribed herein are useful, for example as a method of for inhibitingthe degradation of neurons derived from a subject. In some embodiments,one or more compounds and/or compositions as described herein, areuseful for inhibiting the degeneration of a neuron, or portion thereof,cultured in vitro. In some embodiments, one or more compounds and/orcompositions as described herein, are useful as stabilizing agents topromote in vitro neuronal survival.

In some embodiments, one or more compounds and/or compositions asdescribed herein are useful, for example in affecting biomarkersassociated with neurodegeneration. In some embodiments, changes inbiomarkers can be detected systemically or with a sample of cerebralspinal fluid (CSF), plasma, serum, and/or tissue from a subject. In someembodiments, one or more compounds and/or compositions can be used toaffect a change in the concentration of neurofilament protein light(NF-L) and/or neurofilament protein heavy (NF—H) contained the cerebralspinal fluid of a subject. In some embodiments, one or more compoundsand/or compositions as described herein can affect constitutive NADand/or cADPR levels in neurons and/or axons.

In some embodiments, one or more biomarkers of neurodegenerationcomprises: concentration of neurofilament light chain protein (NF-L) inone or more of: a cerebrospinal fluid (CSF) sample, a blood sample, anda plasma sample from the subject; concentration of neurofilament heavychain protein (NF—H) in one or more of: a cerebrospinal fluid (CSF)sample, a blood sample, and a plasma sample from the subject;concentration of Ubiquitin C-terminal Hydrolase L1 (UCH-L1) in one ormore of: a cerebrospinal fluid (CSF) sample, a blood sample, and aplasma sample from the subject; concentration of alpha-synuclein in oneor more of: a cerebrospinal fluid (CSF) sample, a blood sample, and aplasma sample from the subject; constitutive NAD+ levels in neuronsand/or axons of the subject; constitutive cADPR levels in neurons and/oraxons of the subejct; levels of albumin, amyloid-β (Aβ)38, Aβ40, Aβ42,glial fibrillary acid protein (GFAP), heart-type fatty acid bindingprotein (hFABP), monocyte chemoattractin protein (MCP)-1, neurogranin,neuron specific enolayse (NSE), soluble amyloid precursor protein(sAPP)α, sAPPβ, soluble triggering receptor expressed on myeloid cells(sTREM) 2, phospho-tau, or total-tau in one or more of: a cerebrospinalfluid (CSF) sample, a blood sample, a plasma sample, skin biopsy sample,a nerve biopsy sample, and a brain biopsy sample from the subject; andlevels of C-C Motif Chemokine Ligand (CCL)2, CCL7, CCL12, colonystimulating factor (CSF)1, or Interleukin (IL)6 in one or more of: acerebrospinal fluid (CSF) sample, a blood sample, a plasma sample, skinbiopsy sample, a nerve biopsy sample, and a brain biopsy sample from thesubject.

In some embodiments, one or more compounds and/or compositions asdescribed herein can affect a detectable change in the levels of one ormore neurodegeneration-associated proteins in a subject. Such proteinsinclude, but are not limited to, albumin, amyloid-β (Aβ)38, Aβ40, Aβ42,glial fibrillary acid protein (GFAP), heart-type fatty acid bindingprotein (hFABP), monocyte chemoattractin protein (MCP)-1, neurogranin,neuron specific enolayse (NSE), soluble amyloid precursor protein(sAPP)α, sAPPβ, soluble triggering receptor expressed on myeloid cells(sTREM) 2, phospho-tau, and/or total-tau. In some embodiments, one ormore compounds and/or compositions as described herein can affect achange in cytokines and/or chemokines, including, but not limited to,Ccl2, Ccl7, Ccl12, Csf1, and/or Il6.

Diseases, Disorders, and Conditions

In some embodiments, compounds and/or compositions as described hereinmay be administered to subjects suffering from one or more diseases,disorders, or conditions. In some embodiments, the one or more diseases,disorders, or conditions are mediated by SARM1.

In some embodiments, a neurodegenerative disease or disorder comprisesan acute or chronic disease or disorder of the peripheral nervous system(PNS), an acute or chronic disease or disorder of the central nervoussystem (CNS), or a disease associated with neurodegeneration.

In some embodiments, a neurodegenerative disease or disorder comprisesan acute disease or disorder of the PNS. In some embodiments, an acutedisease or disorder of the PNS is the result of a mechanical injury,thermal injury, or injury from a chemical agent or chemotherapy. In someembodiments, a mechanical injury comprises a compression or entrapmentinjury or a pressure injury. In some embodiments, a compression orentrapment injury comprises carpal tunnel syndrome, direct trauma, apenetrating injury, a contusion, a fracture or a dislocated bone. Insome embodiments, a pressure injury comprises pressure involvingsuperficial nerves, pressure from a tumor or increased intraocularpressure. In some embodiments, a chemical agent or chemotherapycomprises a cytotoxic anticancer agent, thalidomide, an epothilone, ataxane, a vinca alkaloid, a proteasome inhibitor, a platinum-based drugor an auristatin. In some embodiments, an epothilone is ixabepilone. Insome embodiments, a taxane is paclitaxel or docetaxel. In someembodiments, a vinca alkaloid is vinblastine, vinorelbine, vincristine,or vindesine. In some embodiments, a proteasome inhibitor is bortezomib.In some embodiments, a platinum-based drug is cisplatin, oxaliplatin, orcarboplatin. In some embodiments, an auristatin is conjugated monomethylauristatin E.

In some embodiments, a neurodegenerative disease or disorder comprises achronic disease or disorder of the PNS. In some embodiments, a chronicdisease or disorder of the PNS comprises a systemic disorder, a paindisorder, or a metabolic disease or disorder.

In some embodiments, a chronic disease or disorder of the PNS comprisesinherited neuropathies, Charcot-Marie-Tooth disease, hereditary sensoryand autonomic neuropathy (HSAN), chronic inflammatory demyelinatingpolyneuropathy (CIDP), idiopathic neuropathies or other peripheralneuropathies.

In some embodiments, a systemic disorder comprises diabetes, uremia,AIDS, leprosy, a nutritional deficiency, atherosclerosis, an entericneuropathy, an axonopathy, Guillain-Barre syndrome, severe acute motoraxonal neuropathy (AMAN), systemic lupus erythematosus, scleroderma,sarcoidosis, rheumatoid arthritis, or polyarteritis nodosa.

In some embodiments, a pain disorder comprises chronic pain,fibromyalgia, spinal pain, carpal tunnel syndrome, pain from cancer,arthritis, sciatica, headaches, pain from surgery, muscle spasms, backpain, visceral pain, pain from injury, dental pain, neurogenic pain,neuropathic pain, nerve inflammation, nerve damage, shingles, herniateddisc, torn ligament, or diabetes.

In some embodiments, a metabolic disease or disorder comprises diabetesmellitus, hypoglycemia, uremia, hypothyroidism, hepatic failure,polycythemia, amyloidosis, acromegaly, porphyria, nonalcoholic fattyliver disease (NAFLD), nonalcoholic steatohepatitis (NASH), disorders oflipid/glycolipid metabolism, a nutritional deficiency, a vitamindeficiency, or a mitochondrial disorder.

In some embodiments, a neurodegenerative disease or disorder comprisesan acute disease or disorder of the CNS. In some embodiments, an acutedisease or disorder of the CNS comprises an ischemia, a traumatic CNSinjury, injury from a chemical agent, thermal injury, or viralencephalitis.

In some embodiments, an ischemia comprises cerebral ischemia, hypoxicdemyelination, ischemic demyelination, ischemic optic neuropathy, ornon-arteritic anterior ischemic optic neuropathy.

In some embodiments, a traumatic CNS injury comprises a spinal cordinjury, a TBI, a mechanical injury to the head and/or spine, a traumaticinjury to the head and/or spine, blunt force trauma, closed head injury,open head injury, exposure to a concussive and/or explosive force, apenetrating injury to the CNS, increased intraocular pressure, or damagefrom a force which causes axons to deform, stretch, crush or sheer.

In some embodiments, a viral encephalitis comprises enterovirusencephalitis, arbovirus encephalitis, herpes simplex virus (HSV)encephalitis, West Nile virus encephalitis, La Crosse encephalitis,Bunyavirus encephalitis, pediatric viral encephalitis, or HIVencephalopathy (HIV-associated dementia).

In some embodiments, a neurodegenerative disease or disorder comprises achronic disease or disorder of the CNS.

In some embodiments, a chronic disease or disorder of the CNS comprisesAlzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis(ALS, Lou Gehrig’s disease), multiple sclerosis (MS), Huntington’sdisease (HD), senile dementia, Pick’s disease, Gaucher’s disease, Hurlersyndrome, progressive multifocal leukoencephalopathy, Alexander’sdisease, congenital hypomyelination, encephalomyelitis, acutedisseminated encephalomyelitis, central pontine myelolysis, osmotichyponatremia, Tay-Sachs disease, motor neuron disease, ataxia, spinalmuscular atrophy (SMA), Niemann-Pick disease, acute hemorrhagicleukoencephalitis, trigeminal neuralgia, Bell’s palsy, cerebralischemia, multiple system atrophy, Pelizaeus Merzbacher disease,periventricular leukomalacia, a hereditary ataxia, noise-induced hearingloss, congenital hearing loss, age-related hearing loss,Creutzfeldt-Jakob disease, transmissible spongiform encephalopathy, LewyBody Dementia, frontotemporal dementia, amyloidosis, diabeticneuropathy, globoid cell leukodystrophy (Krabbe’s disease),Bassen-Kornzweig syndrome, transverse myelitis, motor neuron disease, aspinocerebellar ataxia, pre-eclampsia, hereditary spastic paraplegias,spastic paraparesis, familial spastic paraplegia, French settlementdisease, Strumpell-Lorrain disease, non-alcoholic steatohepatitis(NASH), adrenomyeloneuropathy, progressive supra nuclear palsy (PSP),Friedrich’s ataxia, or spinal cord injury.

In some embodiments, a chronic disease or disorder of the CNS comprisesan optic nerve disorder, a traumatic CNS injury, or a metabolic diseaseor disorder.

In some embodiments, an optic nerve disorder comprises an acute opticneuropathy (AON), a genetic or idiopathic retinal condition, Lebercongenital amaurosis (LCA), Leber hereditary optic neuropathy (LHON),primary open-angle glaucoma (POAG), acute angle-closure glaucoma (AACG),autosomal dominant optic atrophy, retinal ganglion degeneration,retinitis pigmentosa, an outer retinal neuropathy, optic nerve neuritis,optic nerve degeneration associated with multiple sclerosis, Kjer’soptic neuropathy, an ischemic optic neuropathy, a deficiency in vitaminB 12, a deficiency in folic acid (vitamin B9), isolated vitamin Edeficiency syndrome, non-arteritic anterior ischemic optic neuropathy,exposure to ethambutol, or exposure to cyanide.

In some embodiments, a traumatic CNS injury comprises a traumatic braininjury (TBI), a spinal cord injury, traumatic axonal injury or chronictraumatic encephalopathy (CTE).

In some embodiments, a metabolic disease or disorder comprises diabetesmellitus, hypoglycemia, Bassen-Kornzweig syndrome, uremia,hypothyroidism, hepatic failure, polycythemia, amyloidosis, acromegaly,porphyria, disorders of lipid/glycolipid metabolism, nutritional/vitamindeficiencies, and mitochondrial disorders.

In some embodiments, a neurodegenerative disease or disorder comprises adisease associated with neurodegeneration. In some embodiments, aneurodegenerative disease or disorder results from blood clottingissues, inflammation, obesity, aging, stress, cancer, or diabetes.

In some embodiments, the condition is an acute peripheral neuropathy.Chemotherapy-induced peripheral neuropathy (CIPN) is an example of anacute peripheral neuropathy. CIPN can be associated with various drugs,such as, but not limited to, thalidomide, epothilones (e.g.,ixabepilone), taxanes (e.g., paclitaxel and docetaxel), vinca alkaloids(e.g., vinblastine, vinorelbine, vincristine, and vindesine), proteasomeinhibitors (e.g., bortezomib), platinum-based drugs (e.g., cisplatin,oxaliplatin, and carboplatin).

In some embodiments, one or more compounds and/or compositions asdescribed herein are useful, for example, to treat one or moreneurodegenerative diseases, disorders or conditions selected from thegroup consisting of neuropathies and axonopathies. In some embodiments,one or more compounds and/or compositions as described herein areuseful, for example to treat a neuropathy or axonopathy associated withaxonal degeneration. In some embodiments, a neuropathy associated withaxonal degeneration is a hereditary or congenital neuropathy oraxonopathy. In some embodiments, a neuropathy associated with axonaldegeneration results from a de novo or somatic mutation. In someembodiments, a neuropathy associated with axonal degeneration isselected from a list contained herein. In some embodiments, a neuropathyor axonopathy is associated with axonal degeneration, including, but notlimited to Parkinson’s disease, non-Parkinson’s disease, Alzheimer’sdisease, Herpes infection, diabetes, amyotrophic lateral sclerosis, ademyelinating disease, ischemia or stroke, chemical injury, thermalinjury, and AIDS.

In some embodiments, one or more compounds or compositions as describedherein is characterized that, when administered to a population ofsubjects, reduces one or more symptoms or features of neurodegeneration.For example, in some embodiments, a relevant symptom or feature may beselected from the group consisting of extent, rate, and/or timing ofneuronal disruption. In some embodiments, neuronal disruption may be orcomprise axonal degradation, loss of synapses, loss of dendrites, lossof synaptic density, loss of dendritic arborization, loss of axonalbranching, loss of neuronal density, loss of myelination, loss ofneuronal cell bodies, loss of synaptic potentiation, loss ofaction-potential potentiation, loss of cytoskeletal stability, loss ofaxonal transport, loss of ion channel synthesis and turnover, loss ofneurotransmitter synthesis, loss of neurotransmitter release andreuptake capabilities, loss of axon-potential propagation, neuronalhyperexitability, and/or neuronal hypoexcitability. In some embodiments,neuronal disruption is characterized by an inability to maintain anappropriate resting neuronal membrane potential. In some embodiments,neuronal disruption is characterized by the appearance of inclusionbodies, plaques, and/or neurofibrillary tangles. In some embodiments,neuronal disruption is characterized by the appearance of stressgranules. In some embodiments, neuronal disruption is characterized bythe intracellular activation of one or more members of thecysteine-aspartic protease (Caspase) family. In some embodiments,neuronal disruption is characterized by a neuron undergoing programedcell death (e.g. apoptosis, pyroptosis, ferroapoptosis, and/or necrosis)and/or inflammation.

In some embodiments, the neurodegenerative or neurological disease ordisorder is associated with axonal degeneration, axonal damage,axonopathy, a demyelinating disease, a central pontine myelinolysis, anerve injury disease or disorder, a metabolic disease, a mitochondrialdisease, metabolic axonal degeneration, axonal damage resulting from aleukoencephalopathy or a leukodystrophy. In some embodiments, theneurodegenerative or neurological disease or disorder is selected fromthe group consisting of spinal cord injury, stroke, multiple sclerosis,progressive multifocal leukoencephalopathy, congenital hypomyelination,encephalomyelitis, acute disseminated encephalomyelitis, central pontinemyelolysis, osmotic hyponatremia, hypoxic demyelination, ischemicdemyelination, adrenoleukodystrophy, Alexander’s disease, Niemann-Pickdisease, Pelizaeus Merzbacher disease, periventricular leukomalacia,globoid cell leukodystrophy (Krabbe’s disease), Wallerian degeneration,optic neuritis, transverse myelitis, amyotrophic lateral sclerosis (ALS,Lou Gehrig’s disease), Huntington’s disease, Alzheimer’s disease,Parkinson’s disease, Tay-Sacks disease, Gaucher’s disease, HurlerSyndrome, traumatic brain injury, post radiation injury, neurologiccomplications of chemotherapy (chemotherapy induced neuropathy; CIPN),neuropathy, acute ischemic optic neuropathy, vitamin B₁₂ deficiency,isolated vitamin E deficiency syndrome, Bassen-Kornzweig syndrome,Glaucoma, Leber’s hereditary optic atrophy (neuropathy), Lebercongenital amaurosis, neuromyelitis optica, metachromaticleukodystrophy, acute hemorrhagic leukoencephalitis, trigeminalneuralgia, Bell’s palsy, cerebral ischemia, multiple system atrophy,traumatic glaucoma, tropical spastic paraparesis human T-lymphotropicvirus 1 (HTLV-1) associated myelopathy, west Nile virus encephalopathy,La Crosse virus encephalitis, Bunyavirus encephalitis, pediatric viralencephalitis, essential tremor, Charcot-Marie-Tooth disease, motorneuron disease, spinal muscular atrophy (SMA), hereditary sensory andautonomic neuropathy (HSAN), adrenomyeloneuropathy, progressive supranuclear palsy (PSP), Friedrich’s ataxia, hereditary ataxias, noiseinduced hearing loss, congenital hearing loss, Lewy Body Dementia,frontotemporal dementia, amyloidosis, diabetic neuropathy, HIVneuropathy, enteric neuropathies and axonopathies, Guillain-Barresyndrome, severe acute motor axonal neuropathy (AMAN), Creutzfeldt-Jakobdisease, transmissible spongiform encephalopathy, spinocerebellarataxias, pre-eclampsia, hereditary spastic paraplegias, spasticparaparesis, familial spastic paraplegia, French settlement disease,Strumpell-Lorrain disease, and non-alcoholic steatohepatitis (NASH).

In some embodiments, the present disclosure provides inhibitors of SARM1activity for treatment of neurodegenerative or neurological diseases ordisorders that involve axon degeneration or axonopathy. The presentdisclosure also provides methods of using inhibitors of SARM1 activityto treat, prevent or ameliorate axonal degeneration, axonopathies andneurodegenerative or neurological diseases or disorders that involveaxonal degeneration.

In some embodiments, the present disclosure provides methods of treatingneurodegenerative or neurological diseases or disorders related toaxonal degeneration, axonal damage, axonopathies, demyelinatingdiseases, central pontine myelinolysis, nerve injury diseases ordisorders, metabolic diseases, mitochondrial diseases, metabolic axonaldegeneration, axonal damage resulting from a leukoencephalopathy or aleukodystrophy.

In some embodiments, neuropathies and axonopathies include any diseaseor condition involving neurons and/or supporting cells, such as forexample, glia, muscle cells or fibroblasts, and, in particular, thosediseases or conditions involving axonal damage. Axonal damage can becaused by traumatic injury or by non-mechanical injury due to diseases,conditions, or exposure to toxic molecules or drugs. The result of suchdamage can be degeneration or dysfunction of the axon and loss offunctional neuronal activity. Disease and conditions producing orassociated with such axonal damage are among a large number ofneuropathic diseases and conditions. Such neuropathies can includeperipheral neuropathies, central neuropathies, and combinations thereof.Furthermore, peripheral neuropathic manifestations can be produced bydiseases focused primarily in the central nervous systems and centralnervous system manifestations can be produced by essentially peripheralor systemic diseases.

In some embodiments, a peripheral neuropathy can involve damage to theperipheral nerves, and/or can be caused by diseases of the nerves or asthe result of systemic illnesses. Some such diseases can includediabetes, uremia, infectious diseases such as AIDs or leprosy,nutritional deficiencies, vascular or collagen disorders such asatherosclerosis, and autoimmune diseases such as systemic lupuserythematosus, scleroderma, sarcoidosis, rheumatoid arthritis, andpolyarteritis nodosa. In some embodiments, peripheral nerve degenerationresults from traumatic (mechanical) damage to nerves as well as chemicalor thermal damage to nerves. Such conditions that injure peripheralnerves include compression or entrapment injuries such as glaucoma,carpal tunnel syndrome, direct trauma, penetrating injuries, contusions,fracture or dislocated bones; pressure involving superficial nerves(ulna, radial, or peroneal) which can result from prolonged use ofcrutches or staying in one position for too long, or from a tumor;intraneural hemorrhage; ischemia; exposure to cold or radiation orcertain medicines or toxic substances such as herbicides or pesticides.In particular, the nerve damage can result from chemical injury due to acytotoxic anticancer agent such as, for example, taxol, cisplatinin, aproteasome inhibitor, or a vinca alkaloid such as vincristine. Typicalsymptoms of such peripheral neuropathies include weakness, numbness,paresthesia (abnormal sensations such as burning, tickling, pricking ortingling) and pain in the arms, hands, legs and/or feet. In someembodiments, a neuropathy is associated with mitochondrial dysfunction.Such neuropathies can exhibit decreased energy levels, i.e., decreasedlevels of NAD and ATP.

In some embodiments, peripheral neuropathy is a metabolic and endocrineneuropathy which includes a wide spectrum of peripheral nerve disordersassociated with systemic diseases of metabolic origin. These diseasesinclude, for example, diabetes mellitus, hypoglycemia, uremia,hypothyroidism, hepatic failure, polycythemia, amyloidosis, acromegaly,porphyria, disorders of lipid/glycolipid metabolism, nutritional/vitamindeficiencies, and mitochondrial disorders, among others. The commonhallmark of these diseases is involvement of peripheral nerves byalteration of the structure or function of myelin and axons due tometabolic pathway dysregulation.

In some embodiments, neuropathies include optic neuropathies such asglaucoma; retinal ganglion degeneration such as those associated withretinitis pigmentosa and outer retinal neuropathies; optic nerveneuritis and/or degeneration including that associated with multiplesclerosis; traumatic injury to the optic nerve which can include, forexample, injury during tumor removal; hereditary optic neuropathies suchas Kjer’s disease and Leber’s hereditary optic neuropathy; ischemicoptic neuropathies, such as those secondary to giant cell arteritis;metabolic optic neuropathies such as neurodegenerative diseasesincluding Leber’s neuropathy mentioned earlier, nutritional deficienciessuch as deficiencies in vitamins B12 or folic acid, and toxicities suchas due to ethambutol or cyanide; neuropathies caused by adverse drugreactions and neuropathies caused by vitamin deficiency. Ischemic opticneuropathies also include non-arteritic anterior ischemic opticneuropathy.

In some embodiments neurodegenerative diseases that are associated withneuropathy or axonopathy in the central nervous system include a varietyof diseases. Such diseases include those involving progressive dementiasuch as, for example, Alzheimer’s disease, senile dementia, Pick’sdisease, and Huntington’s disease; central nervous system diseasesaffecting muscle function such as, for example, Parkinson’s disease,motor neuron diseases and progressive ataxias such as amyotrophiclateral sclerosis; demyelinating diseases such as, for example multiplesclerosis; viral encephalitides such as, for example, those caused byenteroviruses, arboviruses, and herpes simplex virus; and priondiseases. Mechanical injuries such as glaucoma or traumatic injuries tothe head and spine can also cause nerve injury and degeneration in thebrain and spinal cord. In addition, ischemia and stroke as well asconditions such as nutritional deficiency and chemical toxicity such aswith chemotherapeutic agents can cause central nervous systemneuropathies.

In some embodiments, the present disclosure provides a method oftreating a neuropathy or axonopathy associated with axonal degeneration.In some such embodiments, a neuropathy or axonopathy associated withaxonal degeneration can be any of a number of neuropathies oraxonopathies such as, for example, those that are hereditary orcongenital or associated with Parkinson’s disease, Alzheimer’s disease,Herpes infection, diabetes, amyotrophic lateral sclerosis, ademyelinating disease, ischemia or stroke, chemical injury, thermalinjury, and AIDS. In addition, neurodegenerative diseases not mentionedabove as well as a subset of the above mentioned diseases can also betreated with the methods of the present disclosure. Such subsets ofdiseases can include Parkinson’s disease or non-Parkinson’s diseases, orAlzheimer’s disease.

Subjects

In some embodiments, compounds and/or compositions as described hereinare administered to subjects suffering from or susceptible to a disease,disorder or condition as described herein; in some embodiments, such adisease, disorder or condition is characterized by axonal degeneration,such as one of the conditions mentioned herein.

In some embodiments, a subject to whom a compound or composition isadministered as described herein exhibits one or more signs or symptomsassociated with axonal degeneration; in some embodiments, the subjectdoes not exhibit any signs or symptoms of neurodegeneration.

In some embodiments, provided methods comprise administering a compoundof Formula I/II to a patient in need thereof. In some such embodiments,the patient is at risk of developing a condition characterized by axonaldegeneration. In some embodiments, the patient has a conditioncharacterized by axonal degeneration. In some embodiments, the patienthas been diagnosed with a condition characterized by axonaldegeneration.

In some embodiments, provided methods comprise administering acomposition as described herein to a patient population of in needthereof. In some embodiments, the population is drawn from individualswho engage in activities where the potential for traumatic neuronalinjury is high. In some embodiments, the population is drawn fromathletes who engage in contact sports or other high-risk activities.

In some embodiments, the subject is at risk of developing a conditioncharacterized by axonal degeneration. In some embodiments, the subjectis identified as being at risk of axonal degeneration, e.g., based onthe subject’s genotype, a diagnosis of a condition associated withaxonal degeneration, and/or exposure to an agent and/or a condition thatinduces axonal degeneration.

In some embodiments, the patient is at risk of developing aneurodegenerative disorder. In some embodiments the patient is elderly.In some embodiments, the patient is known to have a genetic risk factorfor neurodegeneration. In some embodiments, the patient has a familyhistory of neurodegenerative disease. In some embodiments, the patientexpresses one or more copies of a known genetic risk factor forneurodegeneration. In some embodiments, the patient is drawn from apopulation with a high incidence of neurodegeneration. In someembodiments, the patient has a hexanucleotide repeat expansion inchromosome 9 open reading frame 72. In some embodiments, the patient hasone or more copies of the ApoE4 allele.

In some embodiments, subjects to which a compound or composition asdescribed herein is administered may be or comprise subjects sufferingfrom or susceptible to a neurodegenerative disease, disorder orcondition. In some embodiments, a neurodegenerative disease, disorder orcondition may be or comprise a traumatic neuronal injury. In someembodiments, a traumatic neuronal injury is blunt force trauma, aclosed-head injury, an open head injury, exposure to a concussive and/orexplosive force, a penetrating injury in to the brain cavity orinnervated region of the body. In some embodiments, a traumatic neuronalinjury is a force which causes the axons to deform, stretch, crush orsheer.

In some embodiments, the subject engages in an activity identified as arisk factor for neuronal degradation, e.g., a subject that engages incontact sports or occupations with a high chance for traumatic neuronalinjury.

For example, the subject may be a patient who is receiving, or isprescribed, a chemotherapy associated with peripheral neuropathy.Examples of chemotherapeutic agents include, but not limited to,thalidomide, epothilones (e.g., ixabepilone), taxanes (e.g., paclitaxeland docetaxel), vinca alkaloids (e.g., vinblastine, vinorelbine,vincristine, and vindesine), proteasome inhibitors (e.g., bortezomib),platinum-based drugs (e.g., cisplatin, oxaliplatin, and carboplatin).

In some embodiments, provided methods comprise administering acomposition as described herein to a patient or patient population basedon the presence or absence of one or more biomarkers. In someembodiments, provided methods further comprise monitoring the level of abiomarker in a patient or patient population and adjusting the dosingregimen accordingly.

Dosing

Those of skill in the art will appreciate that, in some embodiments, theexact amount of a particular compound included in and/or delivered byadministration of a pharmaceutical composition or regimen as describedherein may be selected by a medical practitioner and may be differentfor different subjects, for example, upon consideration of one or moreof species, age, and general condition of the subject, and/or identityof the particular compound or composition, its mode of administration,and the like. Alternatively, in some embodiments, the amount of aparticular compound included in and/or delivered by administration of apharmaceutical composition or regimen as described herein may bestandardized across a relevant patient population (e.g., all patients,all patients of a particular age or stage of disease or expressing aparticular biomarker, etc.).

A provided compound or composition of the present disclosure ispreferably formulated in dosage unit form for ease of administration anduniformity of dosage. The expression “dosage unit form” as used hereinrefers to a physically discrete unit of agent appropriate for thepatient to be treated. It will be understood, however, that the totaldaily usage of a provided compound or composition of the presentdisclosure will be decided by the attending physician within the scopeof sound medical judgment. The specific effective dose level for anyparticular patient or organism will depend upon a variety of factorsincluding the disorder being treated and the severity of the disorder;the clinical condition of the individual patient; the cause of thedisorder; the activity of the specific compound employed; the specificcomposition employed; the age, body weight, general health, sex and dietof the patient; the time of administration, delivery site of the agent,route of administration, and rate of excretion of the specific compoundemployed; the duration of the treatment; drugs used in combination orcoincidental with the specific compound employed, and like factors wellknown in the medical arts. The effective amount of the compound to beadministered will be governed by such considerations, and is the minimumamount necessary to inhibit SARM1 activity as required to prevent ortreat the undesired disease or disorder, such as for example,neurodegeneration or traumatic neural injury.

A pharmaceutically acceptable composition of this disclosure can beadministered to humans and other animals orally, rectally,intravenously, parenterally, intracisternally, intravaginally,intraperitoneally, topically (as by powders, ointments, or drops),bucally, as an oral or nasal spray, or the like, depending on theseverity of the disease, disorder or infection being treated. The dailydose is, in certain embodiments, given as a single daily dose or individed doses two to six times a day, or in sustained release form. Thisdosage regimen may be adjusted to provide the optimal therapeuticresponse. The compounds may be administered on a regimen of 1 to 4 timesper day, preferably once or twice per day.

In some embodiments, compositions of the present disclosure may beadministered orally, parenterally, by inhalation spray, topically,rectally, nasally, buccally, vaginally or via an implanted reservoir.The term “parenteral” as used herein includes subcutaneous, intravenous,intramuscular, intra-articular, intra-synovial, intrasternal,intrathecal, intrahepatic, intradermal, intraocular, intralesional andintracranial injection or infusion techniques. Preferably, thecompositions are administered orally, intraperitoneally orintravenously.

In some embodiments, pharmaceutically acceptable compositions of thisdisclosure may also be administered topically, especially when thetarget of treatment includes areas or organs readily accessible bytopical application, including diseases of the eye, the skin, or thelower intestinal tract. Suitable topical formulations are readilyprepared for each of these areas or organs.

Most preferably, pharmaceutically acceptable compositions of thisdisclosure are formulated for oral administration. Such formulations maybe administered with or without food. In some embodiments,pharmaceutically acceptable compositions of this disclosure areadministered without food. In other embodiments, pharmaceuticallyacceptable compositions of this disclosure are administered with food.

Those additional agents may be administered separately from a providedcompound or composition thereof, as part of a multiple dosage regimen.Alternatively, those agents may be part of a single dosage form, mixedtogether with a provided compound in a single composition. Ifadministered as part of a multiple dosage regime, the two active agentsmay be submitted simultaneously, sequentially or within a period of timefrom one another, normally within five hours from one another.

It should also be understood that a specific dosage and treatmentregimen for any particular patient may depend upon a variety of factors,including the activity of the specific compound employed, the age, bodyweight, general health, sex, diet, time of administration, rate ofexcretion, drug combination, and the judgment of the treating physicianand the severity of the particular disease being treated. In someembodiments, the amount of a compound of the present disclosure in thecomposition will also depend upon the particular compound in thecomposition.

In some embodiments, SARM1 inhibition as described herein may beutilized in combination with one or more other therapies to treat arelevant disease, disorder, or condition. In some embodiments, dosing ofa SARM1 inhibitor is altered when utilized in combination therapy ascompared with when administered as monotherapy; alternatively oradditionally, in some embodiments, a therapy that is administered incombination with SARM1 inhibition as described herein is administeredaccording to a regimen or protocol that differs from its regimen orprotocol when administered alone or in combination with one or moretherapies other than SARM1 inhibition. In some embodiments, compositionswhich comprise an additional therapeutic agent, that additionaltherapeutic agent and a provided compound may act synergistically. Insome embodiments, one or both therapies utilized in a combinationregimen is administered at a lower level or less frequently than when itis utilized as monotherapy.

In some embodiments, compounds and/or compositions described herein areadministered with a chemotherapeutic agent including, but not limitedto, alkylating agents, anthracyclines, taxanes, epothilones, histonedeacetylase inhibitors, topoisomerase inhibitors, kinase inhibitors,nucleotide analogs, peptide antibiotics, platinum-based agents,retinoids, vinca alkaloids and derivatives. In some embodiments,compounds and/or compositions described herein are administered incombination with PARP inhibitors.

Exemplification

The present teachings, including descriptions provided in the Examples,are not intended to limit the scope of any claim. Unless specificallypresented in the past tense, inclusion in the Examples is not intendedto imply that the experiments were actually performed. The followingnon-limiting examples are provided to further illustrate the presentteachings. Those of skill in the art, in light of the presentdisclosure, will appreciate that many changes can be made in thespecific embodiments that are disclosed and still obtain a like orsimilar result without departing from the spirit and scope of thepresent teachings.

Methods

Some methods and compositions described herein utilize laboratorytechniques well known to skilled artisans, and can be found inlaboratory manuals such as Sambrook, J., et al., Molecular Cloning: ALaboratory Manual, 3rd ed. Cold Spring Harbor Laboratory Press, ColdSpring Harbor, N.Y., 2001; Methods In Molecular Biology, ed. Richard,Humana Press, NJ, 1995; Spector, D. L. et al., Cells: A LaboratoryManual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.,1998; and Harlow, E., Using Antibodies: A Laboratory Manual, Cold SpringHarbor Laboratory Press, Cold Spring Harbor, N.Y., 1999. Methods ofadministration of pharmaceuticals and dosage regimens can be determinedaccording to standard principles of pharmacology, using methods providedby standard reference texts such as Remington: the Science and Practiceof Pharmacy (Alfonso R. Gennaro ed. 19th ed. 1995); Hardman, J.G., etal., Goodman & Gilman’s The Pharmacological Basis of Therapeutics, NinthEdition, McGraw-Hill, 1996; and Rowe, R.C., et al., Handbook ofPharmaceutical Excipients, Fourth Edition, Pharmaceutical Press, 2003.

Example 1: Synthesis of Compounds General Synthetic Methods

The compounds according to the present invention and their intermediatesmay be obtained using methods of synthesis which are known to the oneskilled in the art and described in the literature of organic synthesis.Preferably, the compounds are obtained in analogous fashion to themethods of preparation explained more fully hereinafter, in particularas described in the experimental section. In some cases, the order incarrying out the reaction steps may be varied. Variants of the reactionmethods that are known to the one skilled in the art but not describedin detail here may also be used.

The general processes for preparing the compounds according to theinvention will become apparent to the one skilled in the art studyingthe following schemes. Starting materials may be prepared by methodsthat are described in the literature or herein, or may be prepared in ananalogous or similar manner. Any functional groups in the startingmaterials or intermediates may be protected using conventionalprotecting groups. These protecting groups may be cleaved again at asuitable stage within the reaction sequence using methods familiar tothe one skilled in the art.

Optimum reaction conditions and reaction times may vary depending on theparticular reactants used. Unless otherwise specified, solvents,temperatures, pressures and other reaction conditions may be readilyselected by one of ordinary skill in the art. Specific procedures areprovided in the Synthetic Examples section. Intermediates and productsmay be purified by chromatography on silica gel, recrystallizationand/or reverse phase HPLC (RHPLC). Discrete enantiomers may be obtainedby resolution of racemic products using chiral HPLC. RHPLC purificationmethods used anywhere from 0-100% acetonitrile in water containing 0.1%formic acid, 0.1-0.01% TFA, 10 mM aqueous ammonium bicarbonate or 0.2%aqueous ammonium hydroxide and used one of the following columns:

-   a) Waters Xbridge C18 10 µm 30×100 mm column-   b) Waters Sunfire C18 10 µm 30×100 mm column-   c) Waters Xbridge C18 3.5 µm 50×4.6 mm column-   d) HALO C18 2.7 µm 30×4.6 mm column-   e) Waters Sunfire C18 3.5 µm 50×4.6 mm column

Synthetic Examples Synthesis of Indazole, Azaindazole, and IndoleIntermediates

To a mixture of R-1 (3.5 g, 19.9 mmol) in DMF (30 mL) was added NIS(5.37 g,19.9 mmol). The mixture was stirred at rt for 12 h then water(40 ml) was added. The solid was filtered, and dried to afford I-1 (5.0g, 85%).

To a solution of R-2 (950 mg, 5.36 mmol) in DMF (10 mL) was added K₂CO₃(2.22 g, 16.09 mmol) and I₂ (4.08 g, 16.09 mmol). The reaction mixturewas stirred at 30° C. for 16 h, then ice cold water was added (50 mL)and extracted with EtOAc (30 mL × 3). The combined EtOAc extracts wereconcentrated and the residue was purified by flash chromatography (SiO₂,MeOH/CH₂Cl₂ 1:50 to 1:25) to afford the 1-2 (1.4 g, 82%).

To a solution of R-3 (1 g, 5.6 mmol, 1 eq) in DMF (15 mL) was added NIS(2.5 g, 11.2 mmol, 2 eq), then the mixture was stirred at 80° C. for 2h. The reaction mixture was cooled to room temperature, diluted with H₂O(20 mL), and extracted with EtOAc (30 mL × 3). The combined organicphase was washed with brine, dried with NaSO₄, filtered, andconcentrated under reduced pressure. The crude product was purified bythe flash chromatography (SiO₂, petroleum ether: EtOAc from 10: 1 to1: 1) to give 1-3 (1.5 g, 89%).

To a cold (ice bath) mixture of R-4 (9.1 g, 55.15 mmol) andcesiumcarbonate (35.85 g, 100.3 mmol) in DMF (80 mL) was added dropwiseiodomethane (7.83 g, 55.15 mmol) then allowed to warm to rt and stirredfor 18 hrs. The reaction mixture was filtered and the filtrate wasdiluted with water (120 mL) and extracted with ethyl acetate (3 × 200mL). The combined organic layers were dried over sodium sulfate andevaporated under reduced pressure. The residue was purified by flashchromatography (SiO₂, petroleum ether: EtOAc 70:1 to 50:1) to afford themethyl ester (6.1 g, 62%).

To a mixture of the methyl ester (6.1 g, 34.08 mmol) in AcOH (48 mL) wasadded dropwise sodium nitrite (3.1 g, 94.88 mmol) in water (6 mL) atroom temperature and stirred at room temperature for 18 hrs. Thereaction mixture was evaporated, diluted with water (20 mL), adjustedpH=8 with sat. aqueous sodium bicarbonate, and extracted with ethylacetate (3 × 120 mL). The combined organic layers were dried over sodiumsulfate and evaporated under reduced pressure. The residue was purifiedby flash chromatography (SiO₂, petroleum ether: EtOAc 50:1 to 15:1) toafford the indazole (3.3 g, 67%).

To the mixture of indazole (3.3 g, 17.37 mmol) in DMF (30 mL) was addedNIS (5.97 g, 34.74 mmol) at room temperature, and stirred at 50° C. for18 hrs. The reaction mixture was cooled to rt, treated with water (100mL), and extracted with ethyl acetate (3 × 100 mL). The combined organiclayers were washed with water (80 mL) and brine (80 mL), dried oversodium sulfate and evaporated under reduced pressure. The residue waspurified by flash chromatography (SiO₂, petroleum ether: EtOAc 50:1 to15:1) to afford 1-4(4 g, 73%).

To a cold (ice bath) mixture of R-5 (2.3 g, 9.5 mmol) in MeOH (50 mL)was slowly added SOCl₂ (2.2 ml, 30 mmol) then mixture was heated atreflux overnight. The mixture was concentrated to dryness, and thenpurified by flash chromatography (SiO₂, EtoAc in petroleum ether) togive the ester that was dissolved in CHCl₃ (10 mL), cooled in an icebath, then treated with acetic anhydride (1 mL, 11.4 mmol) slowly. Afterthe addition was complete, the reaction mixture was stirred at roomtemperature for 1 h. KOAc (145 mg, 1.4 mmol) was added, followed bytert-butyl nitrite (1 ml, 9.8 mmol). The reaction mixture was heatedunder reflux overnight. The mixture was cooled to room temperature. Theprecipitate was filtered, and then purified by flash chromatography(SiO₂, petroleum ether: EtOAc) to afford 1-5 (450 mg, 36%).

A mixture of 1-5 (450 mg, 1.77 mmol), trimethylboroxine (0.6 ml, 3.54mmol), and PdCl₂(dppf) (130 mg, 0.17 mmol) and K₂CO₃ (733 mg, 5.3 mmol)in dioxane (10 ml) was flushed with N₂ and then stirred at 100° C. for12 h. Water (6 ml) was added, and extracted with EtOAc (50 mL × 3). Thecombined EtOAc was washed with brine, concentrated in vacuo and theresidue was purified by flash chromatography (SiO₂, petroleum ether:EtOAc) to afford the methyl indazole. The methyl indazole was dissolvedin DMF (2 mL), treated with NIS (450 mg, 2 mmol), and heated at 30° C.overnight. Water (5 ml) was added and the solid was filtered to afford1-6 (365 mg, 88%).

To a solution of R-6 (830 mg, 5.06 mmol) in MeOH (20 ml) was addeddropwise SOCl₂ (2 ml) at 0° C. The mixture was stirred at 90° C. for 20h. The reaction mixture was concentrated in vacuo. The residue wastreated with water (5 mL), and adjusted the pH to 9-10 with NaHCO₃solution, and then extracted with ethyl acetate (50 mL × 3). Thecombined organic layers were dried over sodium sulfate, filtered, andevaporated under reduced pressure to afford the ester that dissolved inDMF (8 mL). To this solution was added NIS (1.09 g, 4.86 mmol) andmixture was heated at 70° C. for 16 h. The reaction mixture was pouredinto water (15 mL), and the suspension was filtered to afford 1-7 (1.13g, 92%).

Synthesis of Exemplary Compounds

A mixture of I-1 (2 g, 6.6 mmol), pyridin-4-ylboronic acid (978 mg, 7.9mmol), K₂CO₃ (2.74 g, 19.84 mmol) and PdCl₂(dppf) (448 mg, 0.62 mmol) indioxane (30 mL) and H₂O (5 ml) was flushed with N₂ then stirred at 80°C. overnight. The mixture was treated with water (30 ml), extracted withEtOAc (50 ml × 3), washed with brine, and concentrated in vacuo. Theresidue was purified by flash chromatography (SiO₂, MeOH in CH₂Cl₂ 0 to4%) to afford a residue that was dissolved in THF/water (25 mL/ 5 mL),treated with LiOH (996 mg, 23.6 mmol) and stirred for 12 h at 30° C. Themixture was concentrated in vacuo to afford 1-8 (380 mg, 40%).

The mixture of 1-8 (90 mg, 0.38 mmol), HATU (172 mg,0.45 mmol), andDIPEA (0.13 ml) in DMF (2 mL) was stirred at rt for 0.5 h. Then(4-chloro-3-fluorophenyl)methanamine (0.05 ml, 0.38 mmol) was added. Themixture was stirred at rt for 2 h. Water (15 ml) was added, and thesolid was collected by filtration, and then purified by prep-HPLCExample 16 (23 mg, 15%).

The following examples were prepared in similar fashion from theappropriate halides, boronic acids/esters and amines:

Example Halide Boronic acid/ester Amine 1 I-1

2 I-1

3 I-1

4 I-2

5 I-3

6 I-2

7 I-3

8 I-1

9 I-1

10 I-1

11 I-1

12 I-1

13 I-1

14 I-7

15 I-1

17 I-1

22

24 I-4

25 I-6

To a solution of I-1 (700 mg, 2.31 mmol, 1 eq) in MeOH (8 mL) and H₂O (8mL) was added LiOH (475 mg, 11.5 mmol, 5 eq), and then stirred at roomtemperature overnight. The mixture was concentrated to dryness. Theresidue was treated with water (20 mL), and adjusted to pH = 5 withdilute HC1, and then extracted with EtOAc (20 mL × 3). The organiccombined layers were concentrated to give the acid (700 mg, 2.4 mmol, 1eq) that was dissolved in DCM (10 mL) and treated with (4-chlorophenyl)methanamine (676 mg, 4.8 mmol, 2 eq), propanephosphonic acid anhydride(1.5 g, 4.8 mmol, 2 eq), and Et₃N (928 mg, 7.2 mmol, 3 eq). The mixturewas stirred at 30° C. for 16 h then treated with H₂O (20 mL) andextracted with EtOAc (20 mL × 3). The organic layer was concentratedunder reduced pressure and residue was purified by flash chromatography(SiO₂, petroleum ether: EtOAc from 0 to 50%) to give 1-9 (380 mg, 39%).

To the mixture of I-9 (70 mg, 0.17 mmol, 1 eq),1-methyl-5-(4,4,5,5-tetramethyl-1.3,2-dioxaborolan-2-yl)-1H-imidazole(70 mg, 0.34 mmol, 2 eq) in dioxane (3 mL) and H₂O (0.5 mL) was addedPdCl₂(dppf) (124 mg, 0.17 mmol, 1 eq) and K₂CO₃ (70 mg, 0.51 mmol, 3eq). The mixture was stirred at 110° C. for 16 h under N₂. The reactionmixture was filtered. The filtrate was purified by Prep-HPLC to giveExample 20 (35 mg, 56%).

The following examples were prepared in similar fashion from theappropriate halides, boronic acids/esters and amines:

Example Halide Boronic acid/ester Amine 18 I-1

19 I-1

21 I-1

23 I-1

Example 2 Characterization of Compounds LCMS Methods Analytical LC/MSAnalysis Method A

-   ESI +/- ion mode 150-850 Da-   Column: Phenomenex Kinetix-XB C18, PartNo.00D-4498-AN, 2.1×100 mm,    1.7 µm-   Temperature: 40° C.

Gradient Time (min) 0.1% formic acid in water acetonitrile Flow (mL/min)0 95% 5% 0.6 5.30 0% 100% 0.6 5.80 0% 100% 0.6 5.82 95% 5% 0.6 7.00 95%5% 0.6

Analytical LC/MS Analysis Method B

-   ESI +/- ion mode 150-850 Da-   Column: Phenomenex Gemini-NX C18, Part No. 00D-4453-B0, 2.0×100 mm,    3.0 µm-   Temperature: 40° C.

Gradient Time (min) 2 mM aqueous ammonium bicarbonate acetonitrile Flow(mL/min) 0 95% 5% 0.6 5.50 0% 100% 0.6 5.90 0% 100% 0.6 5.92 95% 5% 0.67.00 95% 5% 0.6

Analytical LC/MS Analysis Method C

-   ESI +/- ion mode 100-1000 Da-   Column: Waters UPLC® BEH™ C18, Part No. 186002352, 2.1×100 mm, 1.7    µm-   Temperature: 40° C.

Gradient Time (min) 2 mM aqueous ammonium bicarbonate acetonitrile Flow(mL/min) 0 95% 5% 0.6 5.30 0% 100% 0.6 5.80 0% 100% 0.6 5.82 95% 5% 0.67.00 95% 5% 0.6

Analytical LC/MS Analysis Method D

-   ESI +/- ion mode 100-1000 Da-   Column: XBridge C18, 3.5 µm 4.6×50 mm-   Temperature: 40° C.

Gradient Time (min) 10 mM aqueous ammonium bicarbonate Acetonitrile Flow(mL/min) 0.00 95% 5% 2.0 1.20 5% 95% 2.0

Analytical LC/MS Analysis Method E

-   ESI +/- ion mode 100-1000 Da-   Column: XBridge SB-C18, 3.5 µm 4.6×50 mm-   Temperature: 40° C.

Gradient Time (min) 10 mM aqueous ammonium bicarbonate Acetonitrile Flow(mL/min) 0.00 95% 5% 2.0 1.40 5% 95% 2.0 4.30 5% 95% 2.0

Analytical LC/MS Analysis Method F

-   ESI +/- ion mode 100-1000 Da-   Column: Sunfire C18, 3.5 µm 4.6×50 mm-   Temperature: 50° C.

Gradient Time (min) 10 mM aqueous ammonium bicarbonate Acetonitrile Flow(mL/min) 0.00 95% 5% 2.0 1.40 5% 95% 2.0 3.00 5% 95% 2.0

Analytical LC/MS Analysis Method G:

-   ESI +/- ion mode 100-1000 Da-   Column: Waters UPLC® BEH™ C18, Part No. 186005297, 1.7 µm 2.1×50 mm-   Temperature: 40° C.

Gradient Time (min) 0.1% formic acid in water 0.1% formic acid inAcetonitrile Flow (mL/min) 0.00 95% 5% 0.9 1.10 0% 100% 0.9 1.35 0% 100%0.9 1.40 95% 5% 0.9 1.50 95% 5% 0.9

Analytical LC/MS Analysis Method H

-   ESI +/- ion mode 100-1000 Da-   Column: Sunfire C18, 3.5 µm 4.6×50 mm-   Temperature: 50° C.

Gradient Time (min) 0.01% TFA in water 0.01% TFA in Acetonitrile Flow(mL/min) 0.00 95% 5% 2.0 1.30 5% 95% 2.0

Analytical LC/MS Analysis Method I

-   ESI +/- ion mode 100-1000 Da-   Column: XBridge C18, 3.5 µm 4.6×50 mm-   Temperature: 40° C.

Gradient Time (min) 0.01% TFA in water 0.01% TFA in Acetonitrile Flow(mL/min) 0.00 95% 5% 2.0 1.30 5% 95% 2.0

Analytical LC/MS Analysis Method J

-   ESI +/- ion mode 100-1000 Da-   Column: XBridge C18, 3.5 µm 4.6×50 mm-   Temperature: 45° C.

Gradient Time (min) 0.1% TFA in water 0.1% TFA in Acetonitrile Flow(mL/min) 0.00 95% 5% 1.7 1.30 5% 95% 1.7 3.00 5% 95% 1.7

Results are presented in Table 1:

TABLE 1 Example LCMS method RT (min) Mol ion (m/z) 1 D 1.71 363 2 E 1.58329 3 D 1.38 365 4 H 1.48 364.1 5 D 1.67 364 6 H 1.39 330.2 7 I 1.34330.2 8 E 1.57 377.1 9 E 1.35 364 10 E 1.55 381 11 D 1.53 282 12 D 1.8399

Example 3: ARM-SAM-TIR SARM1 IC50 Assay

This Example describes an assay of ARM-SAM-TIR NADase activity and useof this assay to measure the efficacy of compounds of Formula I/II toblock SARM1 mediated NAD+ cleavage. This assay was optimized in such away as to characterize the efficacy of the compounds in Formula I/IItoinhibit SARM1 activity and to calculate an IC50 value for each compound.This assay makes use of full length SARM1, which encompasses the ARM,SAM and TIR domains. As demonstrated herein, expression of this fragmentwithout the autoinhibitory N- terminal domain generates a constitutivelyactive enzyme that cleaves NAD+.

Preparation of ARM-SAM-TIR lysate (STL).

NRK1-HEK293T cells were seeded onto 150 cm² plates at 20 × 106 cells perplate. The next day, the cells were transfected with 15 µg ARM-SAM-TIRexpression plasmid, SEQ ID NO: 1.

GCGATCGCGGCTCCCGACATCTTGGACCATTAGCTCCACAGGTATCTTCTTCCCTCTAGTGGTCATAACAGCAGCTTCAGCTACCTCTCAATTCAAAAAACCCCTCAAGACCCGTTTAGAGGCCCCAAGGGGTTATGCTATCAATCGTTGCGTTACACACACAAAAAACCAACACACATCCATCTTCGATGGATAGCGATTTTATTATCTAACTGCTGATCGAGTGTAGCCAGATCTAGTAATCAATTACGGGGTCATTAGTTCATAGCCCATATATGGAGTTCCGCGTTACATAACTTACGGTAAATGGCCCGCCTGGCTGACCGCCCAACGACCCCCGCCCATTGACGTCAATAATGACGTATGTTCCCATAGTAACGCCAATAGGGACTTTCCATTGACGTCAATGGGTGGAGTATTTACGGTAAACTGCCCACTTGGCAGTACATCAAGTGTATCATATGCCAAGTACGCCCCCTATTGACGTCAATGACGGTAAATGGCCCGCCTGGCATTATGCCCAGTACATGACCTTATGGGACTTTCCTACTTGGCAGTACATCTACGTATTAGTCATCGCTATTACCATGCTGATGCGGTTTTGGCAGTACATCAATGGGCGTGGATAGCGGTTTGACTCACGGGGATTTCCAAGTCTCCACCCCATTGACGTCAATGGGAGTTTGTTTTGGCACCAAAATCAACGGGACTTTCCAAAATGTCGTAACAACTCCGCCCCATTGACGCAAATGGGCGGTAGGCGTGTACGGTGGGAGGTCTATATAAGCAGAGCTGGTTTAGTGAACCGTCAGATCAGATCTTTGTCGATCCTACCATCCACTCGACACACCCGCCAGCGGCCGCTGCCAAGCTTCCGAGCTCTCGAATTCAAAGGAGGTACCCACcatgGCCATGCATCACCACCACCATCATAGCTCCGGCGTCGACCTCGGCACCGAGAATTTATATTTCCAAAGCGGCCTCAATGATATCTTCGAGGCCCAGAAGATCGAGTGGCACGAGGGCAGCTCCGACCTCGCCGTGCCCGGTCCCGATGGAGGCGGAGGCACTGGTCCTTGGTGGGCTGCTGGCGGCAGAGGCCCTAGAGAAGTGAGCCCCGGTGCTGGCACCGAGGTGCAAGACGCTCTGGAGAGGGCTCTGCCCGAACTGCAGCAAGCTCTGTCCGCTTTAAAGCAAGCTGGAGGAGCTAGAGCCGTCGGCGCCGGACTGGCCGAAGTGTTCCAGCTCGTGGAGGAAGCTTGGTTATTACCCGCTGTGGGAAGAGAGGTCGCCCAAGGTCTGTGTGACGCCATTCGTCTGGACGGAGGTTTAGACTTATTACTGAGGCTGCTGCAAGCTCCCGAACTGGAGACAAGGGTCCAAGCTGCTCGTCTGCTGGAGCAGATCCTCGTGGCCGAGAATCGTGACAGAGTGGCTAGAATCGGTTTAGGCGTCATCCTCAATTTAGCCAAAGAGAGGGAGCCCGTTGAGCTGGCCAGAAGCGTCGCTGGCATCCTCGAGCACATGTTCAAGCATTCCGAGGAGACTTGTCAGAGACTGGTCGCCGCCGGAGGACTCGATGCTGTTTTATACTGGTGCAGAAGGACAGACCCCGCTTTACTGAGGCATTGTGCTCTGGCCCTCGGCAATTGCGCTTTACATGGAGGCCAAGCCGTCCAGAGAAGGATGGTGGAGAAAAGAGCCGCCGAGTGGCTGTTCCCTTTAGCCTTCTCCAAAGAAGACGAACTGTTACGTCTGCATGCTTGTCTCGCTGTCGCTGTTTTAGCCACCAACAAGGAGGTGGAAAGGGAAGTGGAAAGAAGCGGAACACTGGCTTTAGTCGAACCTCTGGTGGCTTCTTTAGATCCCGGAAGGTTTGCCAGATGTCTGGTCGACGCCAGCGATACCTCCCAAGGAAGAGGCCCCGACGATCTCCAGAGACTGGTGCCTCTGCTGGACAGCAATCGTCTGGAGGCCCAATGTATTGGCGCCTTCTATCTCTGCGCCGAAGCCGCCATCAAGTCTTTACAAGGTAAGACCAAGGTGTTCTCCGACATTGGAGCCATCCAATCTTTAAAGAGGCTGGTGAGCTATTCCACCAACGGCACAAAAAGCGCTTTAGCCAAAAGAGCTTTAAGACTGCTGGGCGAAGAGGTGCCTAGGCCCATTTTACCTTCCGTGCCTAGCTGGAAGGAGGCCGAGGTGCAGACTTGGCTGCAGCAGATCGGCTTTAGCAAATATTGCGAATCCTTTAGGGAGCAGCAAGTTGACGGCGATTTATTATTAAGGCTGACCGAGGAAGAGCTCCAGACAGATTTAGGCATGAAAAGCGGCATCACTCGTAAGAGGTTCTTTCGTGAGCTCACCGAACTGAAGACCTTCGCCAACTACTCCACTTGTGATCGTAGCAATTTAGCTGATTGGCTCGGATCCCTCGATCCCAGATTTCGTCAGTACACCTATGGACTCGTCTCTTGTGGACTGGACAGATCTTTACTGCATCGTGTGAGCGAGCAACAGCTGCTGGAAGATTGCGGCATCCATTTAGGAGTGCACAGAGCCAGAATTCTGACCGCCGCTAGAGAGATGCTGCATTCCCCTCTCCCTTGTACCGGAGGCAAGCCTAGCGGAGACACCCCCGACGTGTTCATCAGCTATCGTAGAAACAGCGGAAGCCAGCTGGCCTCTTTACTGAAGGTCCATTTACAGCTGCACGGATTTAGCGTCTTCATCGACGTGGAGAAACTGGAGGCTGGCAAGTTCGAGGACAAGCTGATCCAGTCCGTGATGGGCGCTAGGAATTTCGTTTTAGTGCTCAGCCCCGGCGCTCTGGATAAATGCATGCAAGATCATGACTGTAAGGACTGGGTCCACAAGGAAATCGTGACCGCTCTGTCTTGTGGCAAGAACATCGTCCCCATCATCGACGGCTTCGAATGGCCCGAGCCTCAAGTTCTCCCCGAAGATATGCAAGCTGTTTTAACCTTCAATGGAATCAAGTGGAGCCACGAGTACCAAGAAGCCACAATCGAGAAGATCATTCGTTTTCTGCAAGGTAGATCCTCCAGAGATTCCTCCGCTGGCAGCGACACATCTTTAGAGGGCGCCGCCCCTATGGGTCCTACCTAATAATctagAAGTTGTCTCCTCCTGCACTGACTGACTGATACAATCGATTTCTGGATCCGCAGGCCTCTGCTAGCTTGACTGACTGAGATACAGCGTACCTTCAGCTCACAGACATGATAAGATACATTGATGAGTTTGGACAAACCACAACTAGAATGCAGTGAAAAAAATGCTTTATTTGTGAAATTTGTGATGCTATTGCTTTATTTGTAACCATTATAAGCTGCAATAAACAAGTTAACAACAACAATTGCATTCATTTTATGTTTCAGGTTCAGGGGGAGGTGTGGGAGGTTTTTTAAAGCAAGTAAAACCTCTACAAATGTGGTATTGGCCCATCTCTATCGGTATCGTAGCATAACCCCTTGGGGCCTCTAAACGGGTCTTGAGGGGTTTTTTGTGCCCCTCGGGCCGGATTGCTATCTACCGGCATTGGCGCAGAAAAAAATGCCTGATGCGACGCTGCGCGTCTTATACTCCCACATATGCCAGATTCAGCAACGGATACGGCTTCCCCAACTTGCCCACTTCCATACGTGTCCTCCTTACCAGAAATTTATCCTTAAGGTCGTCAGCTATCCTGCAGGCGATCTCTCGATTTCGATCAAGACATTCCTTTAATGGTCTTTTCTGGACACCACTAGGGGTCAGAAGTAGTTCATCAAACTTTCTTCCCTCCCTAATCTCATTGGTTACCTTGGGCTATCGAAACTTAATTAACCAGTCAAGTCAGCTACTTGGCGAGATCGACTTGTCTGGGTTTCGACTACGCTCAGAATTGCGTCAGTCAAGTTCGATCTGGTCCTTGCTATTGCACCCGTTCTCCGATTACGAGTTTCATTTAAATCATGTGAGCAAAAGGCCAGCAAAAGGCCAGGAACCGTAAAAAGGCCGCGTTGCTGGCGTTTTTCCATAGGCTCCGCCCCCCTGACGAGCATCACAAAAATCGACGCTCAAGTCAGAGGTGGCGAAACCCGACAGGACTATAAAGATACCAGGCGTTTCCCCCTGGAAGCTCCCTCGTGCGCTCTCCTGTTCCGACCCTGCCGCTTACCGGATACCTGTCCGCCTTTCTCCCTTCGGGAAGCGTGGCGCTTTCTCATAGCTCACGCTGTAGGTATCTCAGTTCGGTGTAGGTCGTTCGCTCCAAGCTGGGCTGTGTGCACGAACCCCCCGTTCAGCCCGACCGCTGCGCCTTATCCGGTAACTATCGTCTTGAGTCCAACCCGGTAAGACACGACTTATCGCCACTGGCAGCAGCCACTGGTAACAGGATTAGCAGAGCGAGGTATGTAGGCGGTGCTACAGAGTTCTTGAAGTGGTGGCCTAACTACGGCTACACTAGAAGAACAGTATTTGGTATCTGCGCTCTGCTGAAGCCAGTTACCTTCGGAAAAAGAGTTGGTAGCTCTTGATCCGGCAAACAAACCACCGCTGGTAGCGGTGGTTTTTTTGTTTGCAAGCAGCAGATTACGCGCAGAAAAAAAGGATCTCAAGAAGATCCTTTGATCTTTTCTACGGGGTCTGACGCTCAGTGGAACGAAAACTCACGTTAAGGGATTTTGGTCATGAGATTATCAAAAAGGATCTTCACCTAGATCCTTTTAAATTAAAAATGAAGTTTTAAATCAATCTAAAGTATATATGAGTAAACTTGGTCTGACAGTTACCAATGCTTAATCAGTGAGGCACCTATCTCAGCGATCTGTCTATTTCGTTCATCCATAGTTGCATTTAAATTTCCGAACTCTCCAAGGCCCTCGTCGGAAAATCTTCAAACCTTTCGTCCGATCCATCTTGCAGGCTACCTCTCGAACGAACTATCGCAAGTCTCTTGGCCGGCCTTGCGCCTTGGCTATTGCTTGGCAGCGCCTATCGCCAGGTATTACTCCAATCCCGAATATCCGAGATCGGGATCACCCGAGAGAAGTTCAACCTACATCCTCAATCCCGATCTATCCGAGATCCGAGGAATATCGAAATCGGGGCGCGCCTGGTGTACCGAGAACGATCCTCTCAGTGCGAGTCTCGACGATCCATATCGTTGCTTGGCAGTCAGCCAGTCGGAATCCAGCTTGGGACCCAGGAAGTCCAATCGTCAGATATTGTACTCAAGCCTGGTCACGGCAGCGTACCGATCTGTTTAAACCTAGATATTGATAGTCTGATCGGTCAACGTATAATCGAGTCCTAGCTTTTGCAAACATCTATCAAGAGACAGGATCAGCAGGAGGCTTTCGCATGAGTATTCAACATTTCCGTGTCGCCCTTATTCCCTTTTTTGCGGCATTTTGCCTTCCTGTTTTTGCTCACCCAGAAACGCTGGTGAAAGTAAAAGATGCTGAAGATCAGTTGGGTGCGCGAGTGGGTTACATCGAACTGGATCTCAACAGCGGTAAGATCCTTGAGAGTTTTCGCCCCGAAGAACGCTTTCCAATGATGAGCACTTTTAAAGTTCTGCTATGTGGCGCGGTATTATCCCGTATTGACGCCGGGCAAGAGCAACTCGGTCGCCGCATACACTATTCTCAGAATGACTTGGTTGAGTATTCACCAGTCACAGAAAAGCATCTTACGGATGGCATGACAGTAAGAGAATTATGCAGTGCTGCCATAACCATGAGTGATAACACTGCGGCCAACTTACTTCTGACAACGATTGGAGGACCGAAGGAGCTAACCGCTTTTTTGCACAACATGGGGGATCATGTAACTCGCCTTGATCGTTGGGAACCGGAGCTGAATGAAGCCATACCAAACGACGAGCGTGACACCACGATGCCTGTAGCAATGGCAACAACCTTGCGTAAACTATTAACTGGCGAACTACTTACTCTAGCTTCCCGGCAACAGTTGATAGACTGGATGGAGGCGGATAAAGTTGCAGGACCACTTCTGCGCTCGGCCCTTCCGGCTGGCTGGTTTATTGCTGATAAATCTGGAGCCGGTGAGCGTGGGTCTCGCGGTATCATTGCAGCACTGGGGCCAGATGGTAAGCCCTCCCGTATCGTAGTTATCTACACGACGGGGAGTCAGGCAACTATGGATGAACGAAATAGACAGATCGCTGAGATAGGTGCCTCACTGATTAAGCATTGGTAACCGATTCTAGGTGCATTGGCGCAGAAAAAAATGCCTGATGCGACGCTGCGCGTCTTATACTCCCACATATGCCAGATTCAGCAACGGATACGGCTTCCCCAACTTGCCCACTTCCATACGTGTCCTCCTTACCAGAAATTTATCCTTAAGATCCCGAATCGTTTAAACTCGACTCTGGCTCTATCGAATCTCCGTCGTTTCGAGCTTACGCGAACAGCCGTGGCGCTCATTTGCTCGTCGGGCATCGAATCTCGTCAGCTATCGTCAGCTTACCTTTTTGGCA (SEQ ID NO: 1).

The cultures were supplemented with 1 mM NR at time of transfection tominimize toxicity from ARM-SAM-TIR overexpression. Forty-eight hoursafter transfection, cells were harvested, pelleted by centrifugation at1,000 rpm (Sorvall ST 16R centrifuge, Thermo Fisher), and washed oncewith cold PBS (0.01 M phosphate buffered saline NaCl 0.138 M; KCl 0.0027M; pH 7.4). The cells were resuspended in PBS with protease inhibitors(cOmplete™ protease inhibitor cocktail, Roche product # 11873580001) andcell lysates were prepared by sonication (Branson Sonifer 450, output =3, 20 episodes of stroke). The lysates were centrifuged (12,000×g for 10min at 4° C.) to remove cell debris and the supernatants (containingARM-SAM-TIR protein) were stored at -80° C. for later use in the invitro ARM-SAM-TIR NADase assay (see below). Protein concentration wasdetermined by the Bicinchoninic (BCA) method and used to normalizelysate concentrations.

ARM-SAM-TIR IC50 Assay of Formula I/II Compounds

The enzymatic assay was performed in a 384-well polypropylene plate inDulbecco’s PBS buffer in a final assay volume of 20 µL. ARM-SAM-TIRlysate with a final concentration of 5 µg/mL was pre-incubated with therespective compound at 1% DMSO final assay concentration over 2 h atroom temperature. The reaction was initiated by addition of 5 µM finalassay concentration of NAD+ as substrate. After a 2 hr room temperatureincubation, the reaction was terminated with 40 µL of stop solution of7.5% trichloroactetic acid in acetonitrile. The NAD+ and ADPRconcentrations were analyzed by a RapidFire High Throughput MassSpectrometry System (Agilent Technologies, Santa Clara, CA) using anAPI4000 triple quadrupole mass spectrometer (AB Sciex Framingham, MA).

Results are presented below in Table 2. Compounds having an activitydesignated as “A” provided an IC₅₀ < 0.1 µM; compounds having anactivity designated as “B” provided an IC₅₀ 0.1-1 µM; compounds havingan activity designated as “C” provided an IC₅₀ 1.01-5 µM; compoundshaving an activity designated as “D” provided an IC₅₀ 5.01-10 µM;compounds having an activity designated as “E” provided an IC₅₀ > 10 µM;nd: not determined.

TABLE 2 Example SARM1 IC₅₀ (µM) 1 A 2 B 3 B 4 A 5 A 6 B 7 C 8 E 9 B 10 A11 B 12 A 13 B

Example 4: Axonal Degeneration Index

This Example illustrates an in vitro axon degeneration assay used tocharacterize compounds of Formula I/II. This assay was used to test theefficacy of the compounds of Formula I/II to prevent axonal degenerationin a mouse dorsal root ganglion (DRG) drop culture.

Mouse DRG Drop culture: Mouse dorsal root ganglion neurons (DRGs) aredissected out of E12.5 CD1 mice (50 ganglion per embryo) and incubatedwith 0.5% Trypsin solution containing 0.02% EDTA (Gibco) at 37° C. for15 min. The cells are then triturated by gentle pipetting and washed 3times with DRG growth medium (Neurobasal medium (Gibco) containing 2%B27 (Invitrogen), 100 ng/ml 2.5S NGF (Harland Bioproducts), 1 mM5-fluoro-2′deoxyuridine (Sigma), penicillin, and streptomycin). Cellsare suspended in the DRG growth medium. DRG drop cultures are created byspotting 5000 cells/well into the center of each well of a 96-welltissue culture plate coated with poly-D-Lysine (0.1 mg/ml; Sigma) andlaminin (3 mg/ml; Invitrogen). Cells are allowed to adhere to the platesin a humidified tissue culture incubator (5% CO₂) for 15 min and thenDRG growth medium was gently added (100 ml well).

Axon degeneration assay: Axonal degeneration is stimulated either bymanual axonal transection using a scalpel blade, or chemotoxic stimuli.After an appropriate experimental time period, the DRG cultures arefixed in 1% PFA plus sucrose and kept in the fridge prior to imaging.Bright-field images of DRG axons and cell bodies are collected using the20x water immersion lens of a Phenix automated confocal microscope(PerkinElmer) and quantitation of axonal performed using in-housedeveloped scripts (Acapella, PerkinElmer).

We claim: 1–8. (canceled)
 9. A compound of Formula II:

or a pharmaceutically acceptable salt thereof, wherein: R¹ is a 5- to6-membered heteroaryl ring having 1-3 heteroatoms independently selectedfrom oxygen, nitrogen, and sulfur, wherein the 5- to 6-memberedheteroaryl ring is optionally substituted with fluorine or methyl; R² isa 5- to 6-membered heteroaryl ring having 1 heteroatom selected fromnitrogen and sulfur, or phenyl, wherein the 5- to 6-membered heteroarylring or phenyl is optionally substituted with 1-2 groups selected fromfluorine and chlorine; R⁴ is hydrogen or methyl; Q is N; X, Y and Z areindependently CR⁵ or a nitrogen atom, provided that no more than two X,Y and Z are nitrogen atoms; and R⁵ is hydrogen or methyl.
 10. Thecompound according to claim 9, which is selected from:

or a pharmaceutically acceptable salt thereof.
 11. A pharmaceuticalcomposition comprising a compound according to claim 9, and apharmaceutically acceptable carrier.
 12. A method comprising a step of:administering a compound according to claim 9 to a subject who (i) has acondition characterized by axonal degeneration or (ii) is at risk ofdeveloping a condition characterized by axonal degeneration.
 13. Amethod of treating or preventing axonal degeneration comprisingadministering to a subject in need thereof a compound according to claim9.
 14. A method of inhibiting SARM1 comprising contacting a biologicalsample with a compound according to claim
 9. 15. A pharmaceuticalcomposition comprising a compound according to claim 10, and apharmaceutically acceptable carrier.
 16. A method comprising a step of:administering a compound according to claim 10 to a subject who (i) hasa condition characterized by axonal degeneration or (ii) is at risk ofdeveloping a condition characterized by axonal degeneration.
 17. Amethod of treating or preventing axonal degeneration comprisingadministering to a subject in need thereof a compound according to claim10.
 18. A method of inhibiting SARM1 comprising contacting a biologicalsample with a compound according to claim 10.